Compounds with antibacterial and antiparasitic properties

ABSTRACT

There are provided novel compounds which have both antibacterial and antiparasitic properties, thereby reducing the need for using several compounds in combined antibacterial and antiparasitic treatment of livestock. The present novel compounds are especially well suited for treatment of coccidiosis, and they are represented by general formula (I) wherein R 1 -R 6 , X and A are as defined in the specification.

FIELD OF THE INVENTION

The present invention relates to novel compounds, pharmaceuticalcompositions containing the same as well as a method for treatment ofbacterial and parasitic disorders, wherein said compounds areadministered.

BACKGROUND OF THE INVENTION

The coccidia are intracellular protozoan parasites which are prevalentin all domestic animals as well as in man. They are the cause ofcoccidiosis, which is characterized by enteritis. Coccidia of the genusEimeria cause severe intestinal infections in poultry and ruminants(cattle, sheep e.t.c.). In fact, coccidiosis is one of the mostfrequently occurring diseases of poultry (see inter alia “PoultryDiseases” by Jordan, F. T. W. and Pattison, M., 4^(th) ed., pp. 261-276,1996, W. B. Saunders Co. Ltd., London, UK). It deserves mentioning thatthe annual costs for anticoccidial medication is about £5 million in theUK only. In poultry, most cases of coccidiosis are caused by protozoabelonging to the genus Eimeria, such as e.g. E. maxima, E. tenella, E.acervulina, E. necatrix, E. hagani, E. praecox, E. mitis and E.brunetti. Other examples of infectious Eimeria protozoa are E.gallopavonis, E. meleagrimitis, E. adenoeides, E. meleagridis, E.dispersa, E. innocua, E. subrotunda, E. truncata, E. anseris, E. bovis,E. zurnii, E. alabamansis, E. auburnensis, E. ashsata, E. parva, E.faurei, E. arloingi, E. debliecki and E. spinosa.

In poultry, e.g. chickens and turkeys, an outbreak of coccidiosis maywith little or no forewarning lead to a serious infection, and unlessthe birds are promptly treated, the result may be a very high mortality.Animals that survive these types of infections are usually of reducedeconomical value, since they become less efficient in converting feed toweight gain, grow much more slowly than normal animals and frequentlyappear listless. A similar disease scenario may also occur upon coccidiainfection of larger animals, e.g. ruminants and pigs, albeit the problemis in general more severe in poultry.

In the treatment of coccidiosis, a recognized problem is the developmentof resistance to known anticoccidial agents. This problem has beenaddressed in numerous publications, such as in Stephen B. et al., Vet.Parasitol., 69(1-2), pp 19-29, 1997.

Thus, there is a general need in the art for both new and improvedantiparasitic compounds, particularly for the treatment of coccidiosis.

Furthermore, antibacterial agents such as enrofloxacin (U.S. Pat. No.4,670,444) are often added to animal feed, and this often leads toresistance problems. Indeed, new antibacterial compounds is an ongoingneed in the art.

Moreover, there is a general public demand to reduce the number of addeddrugs in animal feed.

DISCLOSURE OF THE INVENTION

There are now provided novel compounds which surprisingly have bothantibacterial and antiparasitic properties, thereby reducing the needfor using several prior art compounds in e.g. combined antibacterial andantiparasitic treatment of livestock. Furthermore, the present novelcompounds are especially well suited for treatment of coccidiosis (videinfra). More specifically, the present invention relates to a compoundhaving the general formula (I):

whereinX is selected from F, Cl, I, CN, SH, NO₂, CF₃, COOR₁, CONR₇R₈, NH-aryl,NHSO₂R₁₅ and (CH₂)₁₋₅NHSO₂R₁₅, wherein R₁, R₇, R₈, R₁₅ and aryl are asdefined hereinbelow;R₂-R₃ are independently selected from a group of substituents (a)-(h)consisting of

-   -   (a) H;    -   (b) straight chain, branched or cyclic saturated or unsaturated        alkyl, mono-, di- or trifluoroalkyl, hydroxyalkyl or alkoxyalkyl        having 1-6 carbon atoms;    -   (c) (O-alkyl)_(z), (alkyl-O)_(z)-alkyl, (S-alkyl)_(z),        (alkyl-S)_(z)-alkyl, (alkyl-S—S)_(z)-alkyl, N-(alkyl)_(n),        alkyl-N-(alkyl)_(n), alkyl-NH₂, alkyl-NHSO₂-alkyl or        alkyl-NHSO₂-aryl, where alkyl is as defined in (b) and        optionally contains at least one substituent X, aryl is as        defined in (e), z is an integer from 1 to 5 and n is 1 or 2;    -   (d) (C(O)-alkyl)_(z), (O—C(O)-alkyl)_(z), (S—C(O)-alkyl)_(z) or        (NH—C(O)-alkyl)_(z), where alkyl is as defined in (b) and z as        defined in (c);    -   (e) aryl, condensed aryl or aralkyl, optionally containing at        least one heteroatom selected from N, S and O and/or at least        one substituent selected from X and (a)-(d);    -   (f) O-aryl, C(O)-aryl, C(O)-heteroaryl, O-aralkyl, N-(aryl)_(n),        N-(aralkyl)_(n) or N—(SO₂-aryl)_(n), where aryl is as defined        in (e) and n is 1 or 2;    -   (g) X;    -   (h) NR₇R₈, wherein R₇ and R₈ independently are selected from the        substituents (a)-(f), wherein NR₇R₈ optionally may form a five-        or six-membered saturated or unsaturated ring;        R₁ is selected from the substituents (a)-(b);        A is a radical selected from —N— and —CR₉—, wherein        R₉ is selected from the substituents (a)-(h) or is a C—Y bond to        a radical —YCR₁₀R₁₁CR₁₂R₁₃—, wherein R₁₀-R₁₃ are independently        selected from the substituents (a)-(h) and Y is selected from S,        O and NR₁₄,        wherein R₁₄ is selected from the substituents (a)-(h)        R₄ is selected from the substituents (a)-(h) or may optionally        be a C—C bond to said radical —YCR₁₀R₁₁CR₁₂R₁₃—;        R₅ and R₆ are either independently selected from the        substituents (a)-(h) and a group of substituents (i)-(m)        consisting of    -   (i) furanyl, furyl, pyranyl, piperidinyl, morpholinyl,        pyridinyl, pyrazinyl, piperazinyl and pyrrolidinyl, optionally        containing at least one substituent selected from X and (a)-(d);    -   (j) alkylfuranyl, -furyl, -pyranyl, -piperidinyl, -morpholinyl,        -pyridinyl, -pyrazinyl, -piperazinyl, and -pyrrolidinyl,        optionally containing at least one substituent selected from X        and (a)-(d);    -   (k) SO₂R₁₅, where R₁₅ is selected from the substituents (a)-(f)        and (h)-(j);    -   (l) C(S)—NR₁₆R₁₇ or C(O)—NR₁₆R₁₇, where R₁₆-R₁₇ are        independently selected from the substituents (a)-(k);    -   (m) cycloalkyl-NR₁₆R₁₇, alkylcycloalkyl-NR₁₆R₁₇, cycloalkyl-X or        alkylcycloalkyl-X, where R₁₆ and R₁₇ are as defined in (l) and        the cycloalkyl moiety has 3-7 carbon atoms;        with the proviso that at least one of R₅ and R₆ is selected from        the substituents (c)-(m) and that R₄ is selected from saturated        cycloalkyl and aryl, optionally containing at least one        heteroatom selected from N, S and O and/or at least one        substituent selected from X and (a)-(d);        or taken together with the nitrogen atom to which they are        attached form a group selected from (n)-(p) consisting of        wherein        R₁₈-R₂₁ are independently selected from the substituents        (a)-(b);        R₂₂ is selected from the substituents (c)-(m);        wherein        R₂₃ and R₂₅ are independently selected from the substituents        (a)-(f) or may optionally be part of a C═N bond;        R₂₄ and R₂₆ are independently selected from the group of        substituents (a)-(m) and a group of substituents (q)-(s)        consisting of    -   (q) alkyl-NR₂₇R₂₈, where R₂₇-R₂₈ are independently selected from        the substituents (a)-(m);    -   (r) NR₂₇R₂₀, where R₂₃-R₂₈ are as defined in (q);    -   (s) a ═N═O-alkyl radical;        with the proviso that R₂₃-R₂₅ are not all H when R₂₆ is NH₂, X        is F, A is —CCl—; R₁-R₃ are H and R₄ is cyclopropyl;        with the proviso that at least one of R₂₇ and R₂₈ in (q) is        selected from the substituents (c)-(m) when X is F, A is —COCH₃—        or —N—, R₁-R₃ are H and R₄ is cyclopropyl;        wherein        R₂₇-R₂₈ are as defined in (q), with the proviso that at least        one of R₂₇ and R₂₈ is selected from the substituents (c)-(m);        tautomers, solvates and radiolabelled derivatives thereof; and        pharmaceutically acceptable salts thereof.

As examples of pharmaceutically acceptable salts mention can be made ofacid addition salts, e.g. a salt formed by reaction with hydrohalogenacids, such as hydrochloric acid, sulphuric acid, phosphoric acid,nitric acid, aliphatic, alicyclic, aromatic or hetero-cyclic sulphonicor carboxylic acids, such as formic acid, acetic acid, propionic acid,succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid,citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, pyruvicacid, p-hydroxybenzoic acid, embonic acid, methanesulphonic acid,ethanesulphonic acid, hydroxy-ethanesulphonic acid,halogenbensensulphonic acid, toluenesulphonic acid andnaphtalenesulphonic acid.

In preferred embodiments of the present invention, R₁ is H. Moreover, Xis preferably F.

In one of the most preferred embodiments, a compound according to thepresent invention has the general formula (II):

wherein R₃, R₄, R₉, R₁₉, R₂₁ and R₂₂ are as previously defined.

Preferably, R₃ is selected from a group of substituents consisting of H,CH₃, NH₂, (6-chloro-2-pyridinyl)amino, (6-chloro-2-pyrazinyl)amino,(4-fluorophenyl)sulfonyllamino and [(4-nitrophenyl)sulfonyl]amino.

Preferably, R₄ is selected from a group of substituents consisting ofcyclopropyl, ethyl, 2-fluoroethyl, 4-fluorophenyl and2,4-difluorophenyl.

Preferably, R₉ is either H or F.

Preferably, R₁₉ and R₂₁ are independently either H or CH₃.

Preferably, R₂₂ is selected from a group of substituents consisting of(4-nitroanilino)carbothioyl, anilinocarbothioyl,(4-fluoroanilino)carbothioyl,{4-nitro[(4-nitrophenyl)sulfonyl]anilino}carbothioyl,(4-nitroanilino)carbonyl, (4-fluoroanilino)carbonyl,(4-nitrophenyl)sulfonyl, 6-chloro-2-pyridinyl, 6-chloro-2-pyrazinyl,phenylsulfonyl, (4-methylphenyl)sulfonyl, (4-methoxyphenyl)sulfonyl,2-naphthylsulfonyl, mesitylsulfonyl, propylsulfonyl, benzylsulfonyl,methylsulfonyl, (trifluoromethyl)sulfonyl, (5-bromo-2-thienyl)sulfonyl,(3,5-dichloro-2-hydroxyphenyl)sulfonyl, 5-bromo-2-pyridinyl,3-chloro-2-sulfanylphenyl, (5-chloro-2-thienyl)sulfonyl, 2-pyrazinyl,{4-fluoro[(4-fluorophenyl)sulfonyl]anilino}carbothioyl,{4-fluoro[(4-nitrophenyl)sulfonyl]anilino}carbothioyl,[(6-chloro-2-pyrazinyl)-4-fluoroanilino]carbothioyl,[(6-chloro-2-pyridinyl)-4-fluoroanilino]carbothioyl,(4-fluorophenyl)sulfonyl,6-{[(4-fluorophenyl)sulfonyl]amino}-2-pyridinyl, 4-pyridinylmethyl,4-carboxycyclohexyl, 4-carboxybenzyl, tetrahydro-2-furanylmethyl,4-isopropylphenyl, 2-(1-piperidinyl)ethyl,2-[(2-{[(4-fluorophenyl)sulfonyl]amino}ethyl)disulfanyl]ethyl,2-[(2-{[(4-nitrophenyl)sulfonyl]amino}ethyl)disulfanyl]ethyl,2-[2-({[(4-nitrophenyl)sulfonyl]amino}methoxy)ethoxy]ethyl,2-(2-{[(6-chloro-2-pyrazinyl)amino]methoxy}ethoxy)ethyl,2-(1-pyrrolidinyl)ethyl, (4-nitroanilino)carbothioyl,[3-({[(4-fluorophenyl)sulfonyl]amino}methyl)cyclohexyl]methyl,3-[(3-aminopropyl)(methyl)amino]propyl, 3-aminopropyl,3-{[(trifluoromethyl)sulfonyl]amino}propyl,3-{[(4-nitrophenyl)sulfonyl]amino}propyl,3-(dimethylamino)-2,2-dimethylpropyl, 2-thienylcarboyl,2-aminocyclohexyl, 2-{[(trifluoromethyl)sulfonyl]amino}ethyl,2-{[(4-nitrophenyl)sulfonyl]amino}ethyl,2,2-dimethyl-3-{[(trifluoromethyl)sulfonyl]amino}propyl,phenethylsulfonyl, acetoacetyl, 2-(4-pyridinyl)ethyl,2-(2-pyridinyl)ethyl and 2-methoxy-1-methylethyl.

Most preferably, a compound according to the formula (II) is selectedfrom the compounds disclosed in the following Table 1, the systematicnames of which are also given hereinbelow:

TABLE 1 R₃ R₄ R₉ R₁₉ R₂₁ R₂₂ Denoted H 4-fluoro- H H H (4-nitro- B626phenyl anilino)- carbothioyl H 2-fluoro- F H H (4-nitro- B628 ethylanilino)- carbothioyl CH₃ cyclo- H CH₃ H (4-nitro- B629 propyl anilino)-carbothioyl H ethyl F CH₃ H (4-nitro- B630 anilino)- carbothioyl NH₂cyclo- F H H (4-nitro- B633 propyl anilino)- carbothioyl H 2,4-di- H CH₃H (4-nitro- B634 fluoro- anilino)- phenyl carbothioyl H 2,4-di- H CH₃ H{4-nitro[(4- B635 fluoro- nitrophenyl) phenyl sulfonyl]- anilino}-carbothioyl H ethyl F CH₃ H anilino- B636 carbothioyl H cyclo- H H H(4-fluoro- B637 propyl anilino)- carbothioyl H ethyl H H H (4-nitro-B638 anilino)- carbothioyl H cyclo- H H H (4-nitro- B700 propylanilino)- carbonyl H ethyl F CH₃ H (4-nitro- B702 anilino)- carbonyl H4-fluoro- H H H (4-nitro- JAP 203 phenyl phenyl)- sulfonyl H 4-fluoro- HH H 6-chloro-2- JAP 204 phenyl pyridinyl H 4-fluoro- H H H 6-chloro-2-JAP 205 phenyl pyrazinyl H 2-fluoro- F H H (4-nitro- JAP 206 ethylphenyl)- sulfonyl H 2-fluoro- F H H 6-chloro-2- JAP 207 ethyl pyridinylH 2-fluoro- F H H 6-chloro-2- JAP 208 ethyl pyrazinyl CH₃ cyclo- H CH₃ H(4-nitro- JAP 209 propyl phenyl)- sulfonyl CH₃ cyclo- H CH₃ H6-chloro-2- JAP 210 propyl pyridinyl CH₃ cyclo- H CH₃ H 6-chloro-2- JAP211 propyl pyrazinyl H ethyl F CH₃ H (4-nitro- JAP 213 phenyl)- sulfonylH ethyl F CH₃ H 6-chloro-2- JAP 214 pyridinyl [(4-nitro- cyclo- F H H(4-nitro- JAP 221 phenyl) propyl phenyl)- sulphonyl] sulfonyl amino[(4-nitro- cyclo- F CH₃ CH₃ (4-nitro- JAP 222 phenyl) propyl phenyl)-sulphonyl] sulphonyl amino (6-chloro-2- cyclo- F CH₃ CH₃ 5-chloro-2- JAP223 pyridinyl)- propyl pyridinyl amino (6-chloro-2- cyclo- F CH₃ CH₃6-chloro-2- JAP 224 pyrazinyl)- propyl pyrazinyl amino H 2,4- H CH₃ H(4-nitro- JAP 225 difluoro- phenyl)- phenyl sulfonyl H 2,4- H CH₃ H6-chloro-2- JAP 226 difluoro- pyrazinyl phenyl H 2,4- H CH₃ H6-chloro-2- JAP 227 difluoro- pyridinyl phenyl H cyclo- H H H phenyl- JA1 propyl sulfonyl H cyclo- H H H (4-methyl- JA 2 propyl phenyl)-sulfonyl H cyclo- H H H (4-nitro- JA 3 propyl phenyl)- sulfonyl H cyclo-H H H (4-methoxy- JA 4 propyl phenyl)- sulfonyl H cyclo- H H H2-naphthyl- JA 5 propyl sulfonyl H cyclo- H H H mesityl- JA 6 propylsulfonyl H cyclo- H H H propyl- JA 7 propyl sulfonyl H cyclo- H H Hbenzyl- JA 9 propyl sulfonyl H cyclo- H H H methyl- JA 10 propylsulfonyl H cyclo- H H H (trifluoro- JA 12 propyl methyl)- sulfonyl Hcyclo- H H H (5-bromo-2- JA 13 propyl thienyl)- sulfonyl H cyclo- H H H(3,5-di- JA 14 propyl chloro-2- hydroxy- phenyl)- sulfonyl H ethyl H H H(4-nitro- JA 20 phenyl)- sulfonyl H ethyl H H H (4-methoxy- JA 21phenyl)- sulfonyl H ethyl H H H benzyl- JA 26 sulfonyl H ethyl H H H(3,5- JA 31 dichloro-2- hydroxy- phenyl)- sulfonyl H cyclo- H H H6-chloro-2- JA 39 propyl pyrazinyl H cyclo- H H H 5-bromo-2- JA 40propyl pyridinyl H cyclo- H H H 3-chloro-2- JA 41 propyl sulfanyl-phenyl H cyclo- H H H 6-chloro-2- JA 42 propyl pyridinyl H cyclo- H H H(5-chloro-2- JA 43 propyl thienyl)- sulfonyl H cyclo- H H H 2-pyrazinylJA 46 propyl H cyclo- H H H {4-fluoro- JA 53-2 propyl [(4-fluoro-phenyl)- sulfonyl]- anilino}- carbothioyl H cyclo- H H H {4-fluoro- JA53-3 propyl [(4-nitro- phenyl)- sulfonyl]- anilino}- carbothioyl Hcyclo- H H H [(6-chloro- JA 53-5 propyl 2-pyrazinyl)- 4-fluoro-anilino]- carbothioyl H cyclo- H H H [(6-chloro- JA 53-6 propyl2-pyridinyl)- 4-fluoro- anilino]- carbothioylB626:

6-fluoro-1-(4-fluorophenyl)-7-{4-[(4-nitroanilino)carbothioyl]-1-piperazinyl}-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

B628:

6,8-difluoro-1-(2-fluoroethyl)-7-{4-[(4-nitroanilino)carbothioyl]-1-piperazinyl}-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

B629:

1-cyclopropyl-6-fluoro-5-methyl-7-{3-methyl-4-[(4-nitroanilino)carbothioyl]-1-piperazinyl}-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

B630:

1-ethyl-6,8-difluoro-7-{3-methyl-4-[(4-nitroanilino)carbothioyl]-1-piperazinyl}-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

B633:

5-amino-1-cyclopropyl-6,8-difluoro-7-{4-[(4-nitroanilino)carbothioyl]-1-piperazinyl}-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

B634:

1-(2,4-difluorophenyl)-6-fluoro-7-{3-methyl-4-[(4-nitroanilino)carbothioyl]-1-piperazinyl}-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

B635:

1-(2,4-difluorophenyl)-6-fluoro-7-[3-methyl-4-({4-nitro[(4-nitrophenyl)sulfonyl]anilino}carbothioyl)-1-piperazinyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

B636:

7-[4-(anilinocarbothioyl)-3-methyl-1-piperazinyl]-1-ethyl-6,8-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

B637:

1-cyclopropyl-6-fluoro-7-{4-[(4-fluoroanilino)carbothioyl]-1-piperazinyl}-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

B638:

1-ethyl-6-fluoro-7-{4-[(4-nitroanilino)carbothioyl]-1-piperazinyl}-4-oxo-1,4-dihydro-3-quinolincecarboxylicacid;

JAP 203:

6-fluoro-1-(4-fluorophenyl)-7-{4-[4-nitrophenyl)sulfonyl]-1-piperazinyl}-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JAP 204:

7-[4-(6-chloro-2-pyridinyl)-1-piperazinyl]-6-fluoro-1-(4-fluorophenyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JAP 205:

7-[4-(6-chloro-2-pyrazinyl)-1-piperazinyl]-6-fluoro-1-(4-fluorophenyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JAP 206:

6,8-difluoro-1-(2-fluoroethyl)-7-{4[(4-nitrophenyl)sulfonyl]-1-piperazinyl}-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JAP 207:

7-[4-(6-chloro-2-pyridinyl)-1-piperazinyl]-6,8-difluoro-1-(2-fluoroethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JAP 208:

7-[4-(6-chloro-2-pyrazinyl)-1-piperazinyl]-6,8-difluoro-1-(2-fluoroethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JAP 209:

1-cyclopropyl-6-fluoro-5-methyl-7-{3-methyl-4-[(4-nitrophenyl)sulfonyl]-1-piperazinyl}-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JAP 210:

7-[4-(6-chloro-2-pyridinyl)-3-methyl-1-piperazinyl]-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JAP 211:

7-[4-(6-chloro-2-pyrazinyl)-3-methyl-1-piperazinyl]-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;.

JAP 213:

1-ethyl-6,8-difluoro-7-{3-methyl-4-[(4-nitrophenyl)sulfonyl]-1-piperazinyl}-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JAP 214:

7-[4-(6-chloro-2-pyridinyl)-3-methyl-1-piperazinyl]-1-ethyl-6,8-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JAP 221:

1-cyclopropyl-6,8-difluoro-5-{[(4-nitrophenyl)sulfonyl]amino}-7-{4-[(4-nitrophenyl)sulfonyl]-1-piperazinyl}-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JAP 222:

1-cyclopropyl-7-{3,5-dimethyl-4-[(4-nitrophenyl)sulfonyl]-1-piperazinyl}-6,8-difluoro-5-{[(4-nitrophenyl)sulfonyl]amino}-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JAP 223:

5-[(6-chloro-2-pyridinyl)amino]-7-[4-(6-chloro-2-pyridinyl)-3,5-dimethyl-1-piperazinyl]-1-cyclopropyl-6,8-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JAP 224:

5-[(6-chloro-2-pyrazinyl)amino]-7-[4-(6-chloro-2-pyrazinyl)-3,5-dimethyl-1-piperazinyl]-1-cyclopropyl-6,8-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JAP 225:

1-(2,4-difluorophenyl)-6-fluoro-7-{3-methyl-4-[(4-nitrophenyl)sulfonyl]-1-piperazinyl}-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JAP 226:

7-[4-(6-chloro-2-pyrazinyl)-3-methyl-1-piperazinyl]-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JAP 227:

7-[4-(6-chloro-2-pyridinyl)-3-methyl-1-piperazinyl]-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 1:

1-cyclopropyl-6-fluoro-4-oxo-7-[4-(phenylsulfonyl)-1-piperazinyl]-1,4-dihydro-3-quinolinecarboxylicacid;

JA 2:

1-cyclopropyl-6-fluoro-7-{4-[(4-methylphenyl)sulfonyl]-1-piperazinyl}-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 3:

1-cyclopropyl-6-fluoro-7-{4-[(4-nitrophenyl)sulfonyl]-1-piperazinyl}-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 4:

1-cyclopropyl-6-fluoro-7-{4-[(4-methoxyphenyl)sulfonyl]-1-piperazinyl}-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 5:

1-cyclopropyl-6-fluoro-7-[4-(2-naphthylsulfonyl)-1-piperazinyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 6:

1-cyclopropyl-6-fluoro-7-[4-(mesitylsulfonyl)-1-piperazinyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 7:

1-cyclopropyl-6-fluoro-4-oxo-7-[4-(propylsulfonyl)-1-piperazinyl]-1,4-dihydro-3-quinolinecarboxylicacid;

JA 9:

7-[4-(benzylsulfonyl)-1-piperazinyl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 10:

1-cyclopropyl-6-fluoro-7-[4-(methylsulfonyl)-1-piperazinyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 12:

1-cyclopropyl-6-fluoro-4-oxo-7-{4-[(trifluoromethyl)sulfonyl]-1-piperazinyl}-1,4-dihydro-3-quinolinecarboxylicacid;

JA 13:

7-{4-[(5-bromo-2-thienyl)sulfonyl]-1-piperazinyl}-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 14:

1-cyclopropyl-7-{4-[(3,5-dichloro-2-hydroxyphenyl)sulfonyl]-1-piperazinyl}-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 20:

1-ethyl-6-fluoro-7-{4-[(4-nitrophenyl)sulfonyl]-1-piperazinyl}-4-oxo-1,4-dihydro-3 -quinolinecarboxylic acid;

JA 21:

1-ethyl-6-fluoro-7-{4-[(4-methoxyphenyl)sulfonyl]-1-piperazinyl}-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 26:

7-[4-(benzylsulfonyl)-1-piperazinyl]-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 31:

7-{4-[(3,5-dichloro-2-hydroxyphenyl)sulfonyl]-1-piperazinyl}-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 39:

7-[4-(6-chloro-2-pyrazinyl)-1-piperazinyl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 40:

7-[4-(5-bromo-2-pyridinyl)-1-piperazinyl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 42:

7-[4-(6-chloro-2-pyridinyl)-1-piperazinyl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 43:

7-{4-[(5-chloro-2-thienyl)sulfonyl]-1-piperazinyl}-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 46:

1-cyclopropyl-6-fluoro-4-oxo-7-[4-(2-pyrazinyl)-1-piperazinyl]-1,4-dihydro-3-quinolinecarboxylicacid.

In another preferred embodiment of the present invention, R₉ is a C—Ybond and R₄ is a C—C bond to said radical —YCR₁₀R₁₁CR₁₂R₁₃—. Typically,R₁₀-R₁₃ are H, or R₁₀-R₁₂ are H and R₁₃ is methyl.

In another one of the most preferred embodiments, a compound accordingto the present invention has the general formula (III):

wherein R₁₂, R₁₃ and R₂₂ are as previously defined.

Preferably, Y is either S or O.

Preferably, R₁₂ and R₁₃ are independently either H or CH₃.

Preferably, R₂₂ is selected from the same said group of substituents asthat preferred in the compound(s) of the general formula (II) supra.

Most preferably, a compound according to the formula (III) is selectedfrom the compounds disclosed in the following Table 2, the systematicnames of which are also given hereinbelow:

TABLE 2 Y R₁₂ R₁₃ R₂₂ Denoted O H CH₃ (4-nitrophenyl)sulfonyl JAP 215 OH CH₃ 6-chloro-2-pyridinyl JAP 216 O H CH₃ 6-chloro-2-pyrazinyl JAP 217S H H (4-nitrophenyl)sulfonyl JAP 218 S H H 6-chloro-2-pyridinyl JAP 219S H H 6-chloro-2-pyrazinyl JAP 220 O H CH₃ (4-nitroanilino)carbothioylB631 S H H (4-nitroanilino)carbothioyl B632JAP 215:

9-fluoro-3-methyl-10-{4-[(4-nitrophenyl)sulfonyl]-1-piperazinyl}-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylicacid;

JAP 216:

10-[4-(6-chloro-2-pyridinyl)-1-piperazinyl]-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylicacid;

JAP 217:

10-[4-(6-chloro-2-pyrazinyl)-1-piperazinyl]-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylicacid;

JAP 218:

9-fluoro-10-{4-[(4-nitrophenyl)sulfonyl]-1-piperazinyl}-7-oxo-2,3-dihydro-7H-[1,4]thiazino[2,3,4-ij]quinoline-6-carboxylicacid;

JAP 219:

10-[4-(6-chloro-2-pyridinyl)-1-piperazinyl]-9-fluoro-7-oxo-2,3-dihydro-7H-[1,4]thiazino[2,3,4-ij]quinoline-6-carboxylicacid;

JAP 220:

10-[4-(6-chloro-2-pyrazinyl)-1-piperazinyl]-9-fluoro-7-oxo-2,3-dihydro-7H-[1,4]thiazino[2,3,4-ij]quinoline-6-carboxylicacid;

B631:

9-fluoro-3-methyl-10-{4-[(4-nitroanilino)carbothioyl]-1-piperazinyl}-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylicacid;

B632:

9-fluoro-10-{4-[(4-nitroanilino)carbothioyl]-1-piperazinyl}-7-oxo-2,3-dihydro-7H-[1,4]thiazino[2,3,4-ij]quinoline-6-carboxylicacid.

In another preferred embodiment of the present invention, R₅ and R₆ areselected from the group of substituents (a)-(m). Here, R₄ is typicallycyclopropyl.

In yet another one of the most preferred embodiments, a compoundaccording to the present invention has the general formula (IV):

wherein R₅ and R₆ are as previously defined.

Preferably, R₅ and R₆ are independently selected from H and at least oneof the same said group of substituents as that preferred for R₂₂ in thecompound(s) of the general formula (II) supra.

Most preferably, a compound according to the formula (IV) is selectedfrom the compounds disclosed in the following Table 3, the systematicnames of which are also given hereinbelow:

TABLE 3 R₅ R₆ Denoted {4-fluorophenyl}- 6-{[(4-fluorophenyl)- JA 47-2sulfonyl sulfonyl]amino}-2-pyridinyl H 5-bromo-2-pyridinyl JA 61 H4-pyridinylmethyl JA 68 H 4-carboxycyclohexyl JA 69 6-chloro-2-4-carboxycyclohexyl JA 69-2 pyrazinyl (trifluoromethyl)-4-carboxycyclohexyl JA 69-3 sulfonyl H 4-carboxybenzyl JA 70 Htetrahydro-2-furanylmethyl JA 73 H 4-isopropylphenyl JA 74 H2-(1-piperidinyl)ethyl JA 76 (4-nitrophenyl)- 2-(1-piperidinyl)ethyl JA76-2 sulfonyl 6-chloro-2- 2-(1-piperidinyl)ethyl JA 76-3 pyrazinyl(4-fluorophenyl)- 2-[(2-{[(4-fluorophenyl)- JA 79-2 sulfonylsulfonyl]amino}ethyl)di- sulfanyl]ethyl (4-nitrophenyl)-2-[(2-{[(4-nitrophenyl)- JA 79-3 sulfonyl sulfonyl]amino}ethyl)di-sulfanyl]ethyl (4-nitrophenyl)- 2-[2-({[(4-nitrophenyl)- JA 82-2sulfonyl sulfonyl]amino}methoxy)- ethoxy]ethyl 6-chloro-2-2-(2-{[(6-chloro-2-pyrazinyl)- JA 82-3 pyrazinylamino]methoxy}ethoxy)ethyl phenylsulfonyl 4-pyridinylmethyl JA 91 H2-(1-pyrrolidinyl)ethyl JA 97 (4-nitroanilino)- 2-(1-pyrrolidinyl)ethylJA 97-2 carbothioyl 6-chloro-2- 2-(1-pyrrolidinyl)ethyl JA 97-3pyrazinyl (4-nitrophenyl)- 2-(1-pyrrolidinyl)ethyl JA 97-4 sulfonyl(trifluoromethyl)- 2-(1-pyrrolidinyl)ethyl JA 97-5 sulfonyl(4-fluorophenyl)- [3-({[(4-fluorophenyl)- JA 99-2 sulfonylsulfonyl]amino)methyl)- cyclohexyl]methyl H 3-[(3-aminopropyl)(methyl)-JA 102 amino]propyl H 3-aminopropyl JA 103 (trifluoromethyl)-3-{[(trifluoromethyl)- JA 103-2 sulfonyl sulfonyl]amino)propyl(4-nitrophenyl)- 3-{[(4-nitrophenyl)- JA 103-3 sulfonylsulfonyl]amino}propyl (trifluoromethyl)- 3-(dimethylamino)-2,2- JA 104-2sulfonyl dimethylpropyl 2-thienylcarbonyl 3-(dimethylamino)-2,2- JA104-3 dimethylpropyl H 2-aminocyclohexyl JA 105 (trifluoromethyl)-2-{[(trifluoromethyl)- JA 106-3 sulfonyl sulfonyl]amino)ethyl(4-nitrophenyl)- 2-{[(4-nitrophenyl) - JA 106-4 sulfonylsulfonyl]amino)ethyl (trifluoromethyl)- 2,2-dimethyl-3-{[(trifluoro- JA107-2 sulfonyl methyl)sulfonyl]amino}propyl (4-nitrophenyl)-tetrahydro-2-furanylmethyl JA 117 sulfonyl 2-thienylcarbonyl2-furylmethyl JA 124 2-thienylcarbonyl 2-(1-piperidinyl)ethyl JA 128(4-methoxyphenyl)- tetrahydro-2-furanylmethyl JA 135 sulfonyl2-naphthylsulfonyl tetrahydro-2-furanylmethyl JA 136 phenethylsulfonyltetrahydro-2-furanylmethyl JA 137 (trifluoromethyl)-tetrahydro-2-furanylmethyl JA 138 sulfonyl phenylsulfonyltetrahydro-2-furanylmethyl JA 139 2-thienylcarbonyltetrahydro-2-furanylmethyl JA 140 6-chloro-2- tetrahydro-2-furanylmethylJA 141 pyrazinyl 5-bromo-2- tetrahydro-2-furanylmethyl JA 142 pyridinyl6-chloro-2- tetrahydro-2-furanylmethyl JA 143 pyridinyl acetoacetyltetrahydro-2-furanylmethyl JA 144 2-(4-pyridinyl)-tetrahydro-2-furanylmethyl JA 145 ethyl 2-(2-pyridinyl)-tetrahydro-2-furanylmethyl JA 146 ethyl acetoacetyl2-methoxy-1-methylethyl JA 148 (4-nitrophenyl)- 2-methoxy-1-methylethylJA 149 sulfonyl (4-nitrophenyl)- 4-pyridinylinethyl JA 156 sulfonyl(4-nitrophenyl)- 5-bromo-2-pyridinyl JA 158 sulfonyl (4-fluorophenyl)-5-bromo-2-pyridinyl JA 159 sulfonyl (trifluoromethyl)-5-bromo-2-pyridinyl JA 160 sulfonyl 2-naphtylsulfonyl5-bromo-2-pyridinyl JA 161 2-naphtylsulfonyl tetrahydro-2-furanylmethylJA 162 2-naphtylsulfonyl 4-pyridinylmethyl JA 163 (trifluoromethyl)-4-pyridinylmethyl JA 164 sulfonyl 6-chloro-2- 4-pyridinylmethyl JA 165pyridinyl 6-chloro-2- 4-pyridinylmethyl JA 166 pyrazinyl 5-bromo-2-4-pyridinylmethyl JA 167 pyridinyl (4-nitrophenyl)- 4-carboxybenzyl JA168 sulfonyl 2-naphtylsulfonyl 4-carboxybenzyl JA 169 (trifluoromethyl)-4-carboxybenzyl JA 170 sulfonyl 6-chloro-2- 4-carboxybenzyl JA 171pyridinyl 6-chloro-2- 4-carboxybenzyl JA 172 pyrazinyl 5-bromo-2-4-carboxybenzyl JA 173 pyridinylJA 61:

7-[(5-bromo-2-pyridinyl)amino]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 68:

1-cyclopropyl-6-fluoro-4-oxo-7-[(4-pyridinylmethyl)amino]-1,4-dihydro-3-quinolinecarboxylicacid;

JA 69:

7-[(4-carboxycyclohexyl)amino]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 70:

7-[(4-carboxybenzyl)amino]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 73:

1-cyclopropyl-6-fluoro-4-oxo-7-[(tetrahydro-2-furanylmethyl)amino]-1,4-dihydro-3-quinolinecarboxylicacid;

JA 74:

1-cyclopropyl-6-fluoro-7-(4-isopropylanilino)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 76:

1-cyclopropyl-6-fluoro-4-oxo-7-{[2-(1-piperidinyl)ethyl]-amino}-1,4-dihydro-3-quinolinecarboxylicacid;

JA 91:

1-cyclopropyl-6-fluoro-4-oxo-7-[(phenylsulfonyl)(4-pyridinylmethyl)amino]-1,4-dihydro-3-quinolinecarboxylicacid;

JA 103:

7-[(3-aminopropyl)amino]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 105:

7-[(2-aminocyclohexyl)amino]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 117:

1-cyclopropyl-6-fluoro-7-[[(4-nitrophenyl)sulfonyl](tetrahydro-2-furanylmethyl)amino]-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 135:

1-cyclopropyl-6-fluoro-7-[[(4-methoxyphenyl)sulfonyl](tetrahydro-2-furanylmethyl)amino]-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 136:

1-cyclopropyl-6-fluoro-7-[(2-naphthylsulfonyl)(tetrahydro-2-furanylmethyl)amino]-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 137:

1-cyclopropyl-6-fluoro-4-oxo-7-[(phenethylsulfonyl)(tetrahydro-2-furanylmethyl)amino]-1,4-dihydro-3-quinolinecarboxylicacid;

JA 138:

1-cyclopropyl-6-fluoro-4-oxo-7-{(tetrahydro-2-furanylmethyl)[(trifluoromethyl)sulfonyl]amino}-1,4-dihydro-3-quinolinecarboxylic acid;

JA 139:

1-cyclopropyl-6-fluoro-4-oxo-7-[(phenylsulfonyl)(tetrahydro-2-furanylmethyl)amino]-1,4-dihydro-3-quinolinecarboxylicacid;

JA 141:

7-[(6-chloro-2-pyrazinyl)(tetrahydro-2-furanylmethyl)amino]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 142:

7-[(5-bromo-2-pyridinyl)(tetrahydro-2-furanylmethyl)amino]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 143:

7-[(6-chloro-2-pyridinyl)(tetrahydro-2-furanylmethyl)amino]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 144:

7-[acetoacetyltetrahydro-2-furanylmethyl)amino]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 145:

1-cyclopropyl-6-fluoro-4-oxo-7-[[2-(4-pyridinyl)ethyl](tetrahydro-2-furanylmethyl)amino]-1,4-dihydro-3-quinolinecarboxylicacid;

JA 146:

1-cyclopropyl-6-fluoro-4-oxo-7-[[2-(2-pyridinyl)ethyl](tetrahydro-2-furanylmethyl)amino]-1,4-dihydro-3-quinolinecarboxylicacid;

JA 156:

1-cyclopropyl-6-fluoro-7-[[4-nitrophenyl)sulfonyl](4-pyridinylmethyl)amino]-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 158:

7-{(5-bromo-2-pyridinyl)[(4-nitrophenyl)sulfonyl]amino}-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 159:

7-{(5-bromo-2-pyridinyl)[(4-fluorophenyl)sulfonyl]amino}-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 160:

7-{(5-bromo-2-pyridinyl)[(trifluoromethyl)sulfonyl]amino}-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 161:

7-[(5-bromo-2-pyridinyl)(2-naphtylsulfonyl)amino]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 162:

1-cyclopropyl-6-fluoro-7-[(2-naphtylsulfonyl)(tetrahydro-2-furanylmethyl)amino]-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 163:

1-cyclopropyl-6-fluoro-7-[(2-naphtylsulfonyl)(4-pyridinylmethyl)amino]-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 164:

1-cyclopropyl-6-fluoro-4-oxo-7-{(4-pyridinylmethyl)[(trifluoromethyl)sulfonyl]amino}-1,4-dihydro-3-quinolinecarboxylicacid;

JA 165:

7-[(6-chloro-2-pyridinyl)(4-pyridinylmethyl)amino]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 166:

7-[(6-chloro-2-pyrazinyl)(4-pyridinylmethyl)amino]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 167:

7-[(5-bromo-2-pyridinyl)(4-pyridinylmethyl)amino]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 168:

7-{(4-carboxybenzyl)[(4-nitrophenyl)sulfonyl]amino}-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 169:

7-[(4-carboxybenzyl)(2-naphtylsulfonyl)amino]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 170:

7-{(4-carboxybenzyl)[(trifluoromethyl)sulfonyl]amino}-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 171:

7-[(4-carboxybenzyl)(6-chloro-2-pyridinyl)amino]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 172:

7-[(4-carboxybenzyl)(6-chloro-2-pyrazinyl)amino]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinoline-carboxylicacid;

JA 173:

7-[(5-bromo-2-pyridinyl)(4-carboxybenzyl)amino]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid.

In another preferred embodiment of the present invention, R₅ and R₆ formsaid group (o).

In still another one of the most preferred embodiments, a compoundaccording to the present invention has the general formula (V):

wherein R₄, A and R₂₃-R₂₆ are as previously defined.

Preferably, A is selected from —CCl—, —COCH₃—, and —N—.

Preferably, R₄ is selected from a group of substituents consisting ofcyclopropyl, ethyl, 2-fluoroethyl, 4-fluorophenyl and2,4-difluorophenyl.

Preferably, R₂₃-R₂₆ are independently selected from H and at least oneof a group of substituents consisting of fluoromethyl, methoxyimino,(6-chloro-2-pyridinyl)amino, (6-chloro-2-pyridinyl)[(4-nitrophenyl)sulfonyl]amino, (6-chloro-2-pyrazinyl)[(4-nitrophenyl)sulfonyl]amino, [(4-nitroanilino)carbothioyl]amino,{[(4-nitrophenyl)sulfonyl]amino}methyl,[(6-chloro-2-pyrazinyl)amino]methyl,[(6-chloro-2-pyridinyl)amino]methyl,{[(4-fluoroanilino)carbothioyl]amino}methyl,{({4-fluoro[(4-nitrophenyl)sulfonyl]anilino}carbothioyl)[(4-nitrophenyl)sulfonyl]amino}methyl,{({4-fluoro[(4-methoxyphenyl)sulfonyl]anilino}carbothioyl)[(4-methoxyphenyl)sulfonyl]amino}methyl and the group of substituentspreferred for R₂₂ in the compound(s) of the general formula (II) supra.

Most preferably, a compound according to the formula (V) is selectedfrom the compounds disclosed in the following Table 4, the systematicnames of which are also given hereinbelow:

TABLE 4 R₄ A R₂₃ R₂₄ R₂₅ R₂₆ Denoted cyclo- —CCl— H H H (6-chloro-2- JAP200 propyl pyridinyl)amino cyclo- —CCl— H H H (6-chloro-2-pyridinyl)-JAP 201 propyl [(4-nitrophenyl)- sulfonyl]amino cyclo- —CCl— H H H(6-chloro-2- JAP 202 propyl pyrazinyl)[(4- nitrophenyl)- sulfonyl]aminocyclo- —CCl— H H H [(4-nitroanilino)- B627 propyl carbothioyl]aminocyclo- —COCH₃— H H CH₂F {[(4-nitrophenyl)- JA 1006 propylsulfonyl]amino}- methyl cyclo- —COCH₃— H H CH₂F [(6-chloro-2- JA 1007propyl pyrazinyl)amino]- methyl cyclo- —COCH₃— H H CH₂F [(6-chloro-2- JA1008 propyl pyridinyl)amino]- methyl cyclo- —COCH₃— H H CH₂F{[(4-fluoroanilino)- JA 1009 propyl carbothioyl]- amino}methyl cyclo-—COCH₃— H H CH₂F {[(4-fluoro[(4- JA 1010 propyl nitrophenyl)sulfonyl]-anilino}carbothioyl)- {(4-nitrophenyl)- sulfonyl]- amino}methyl cyclo-—N— ═NOCH₃ H [(6-chloro-2- JA 1012 propyl pyrazinyl)amino]- methylcyclo- —N— ═NOCH₃ H {({4-fluoro[(4- JA 1013 propyl methoxyphenyl)-sulfonyl]anilino}- carbothioyl)[(4- methoxyphenyl)-sulfonyl]amino}methylJAP 200:

8-chloro-7-{3-[(6-chloro-2-pyridinyl)amino]-1-pyrrolidinyl}-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JAP 201:

8-chloro-7-(3-{(6-chloro-2-pyridinyl)[(4-nitrophenyl)sulfonyl]amino}-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JAP 202:

8-chloro-7-(3-{(6-chloro-2-pyrazinyl)[(4-nitrophenyl)sulfonyl]amino)-1-pyrrolidinyl}-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

B627:

8-chloro-1-cyclopropyl-6-fluoro-7-(3-{[(4-nitroanilino)carbothioyl]amino}-1-pyrrolidinyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 1006:

1-cyclopropyl-6-fluoro-7-[3-(fluoromethyl)-3-{[(4-nitrophenyl)sulfonyl]amino}methyl)-1-pyrrolidinyl-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 1007:

7-[3-{[(6-chloro-2-pyrazinyl)amino]methyl}-3-(fluoromethyl)-1-pyrrolidinyl-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 1008:

7-[3-{[(6-chloro-2-pyridinyl)amino]methyl}-3-(fluoromethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 1009:

1-cyclopropyl-6-fluoro-7-[3-({[(4-fluoroanilino)carbothioyl]amino}methyl)-3-(fluoromethyl)-1-pyrrolidinyl]-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 1010:

1-cyclopropyl-6-fluoro-7-[3-(fluoromethyl)-3-({({4-fluoro[(4-nitrophenyl)sulfonyl]anilino}carbothioyl)[(4-nitrophenyl)sulfonyl]amino}methyl)-1-pyrrolidinyl]-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 1012:

7-[3-{[(6-chloro-2-pyrazinyl)amino]methyl}-4-(methoxyimino)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphtyridine-3-carboxylicacid;

JA 1013:

1-cyclopropyl-6-fluoro-7-[3-({({4-fluoro[(4-methoxyphenyl)sulfonyl]anilino}carbothioyl)[(4-methoxyphenyl)sulfonyl]amino}methyl)-4-(methoxyimino)-1-pyrrolidinyl]-4-oxo-1,4-dihydro[1,8]naphtyridine-3-carboxylicacid.

In another preferred embodiment of the present invention, R₅ and R₆ formsaid group (p).

Furthermore, in yet another one of the most preferred embodiments, acompound according to the present invention has the general formula(VI):

wherein A, R₄, R₂₇ and R₂₈ are as previously defined.

Preferably, A is selected from —CCl—, —COCH₃—, and —N—.

Preferably, R₄ is selected from a group of substituent6 consisting ofcyclopropyl, ethyl, 2-fluoroethyl, 4-fluorophenyl and2,4-difluorophenyl.

Preferably, R₂₇ and R₂₈ are independently, selected from H and at leastone of the same said group of substituents as that preferred for R₂₃-R₂₆in the compound(s) of the general formula (V) supra.

Most preferably, a compound according to the formula (VI) is selectedfrom the compounds disclosed in the following Table 5, the systematicnames of which are also given hereinbelow:

TABLE 5 A R₄ R₂₇ R₂₉ Denoted —N— 2,4-di- H (4-fluorophenyl)- JA 1000fluorophenyl sulfonyl —N— 2,4-di- H 6-chloro-2- JA 1001 fluorophenylpyridinyl —N— 2,4-di- H 6-chloro-2- JA 1002 fluorophenyl pyrazinyl —N—2,4-di- H (4-fluoroanilino)- JA 1003 fluorophenyl carbonyl —N— 2,4-di- H(4-fluoroanilino)- JA 1004 fluorophenyl carbothioyl —N— 2,4-di-(4-nitro- {4-fluoro[(4- JA 1005 fluorophenyl phenyl)- nitrophenyl)-sulfonyl sulfonyl]anilino} carbothioylJA 1000:

1-(2,4-difluorophenyl)-6-fluoro-7-(1R,5S)-6-{[(4-fluorophenyl)sulfonyl]amino}-3-azabicyclo[3.1.0]hex-3-yl)-4-oxo-1,4-dihydro1,8]naphtyridine-3-carboxylicacid;

JA 1001:

7-{(1R,5S)-6-[(6-chloro-2-pyridinyl)amino]-3-azabicyclo[3.1.0]hex-3-yl}-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro[1,8]naphtyridine-3-carboxylicacid;

JA 1002:

7-{(1R,5S)-6-[(6-chloro-2-pyrazinyl)amino]-3-azabicyclo[3.1.0]hex-3-yl}-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro[1,8]naphtyridine-3-carboxylicacid;

JA 1003:

1-(2,4-difluorophenyl)-6-fluoro-7-((1R,5S)-6-{[(4-fluoroanilino)carbonyl]amino}-3-azabicyclo[3.1.0]hex-3-yl)-4-oxo-1,4-dihydro[1,8]naphtyridine-3-carboxylicacid;

JA 1004:

1-(2,4-difluorophenyl)-6-fluoro-7-((1R,5S)-6-{[(4-fluoroanilino)carbothioyl]amino}-3-azabicyclo[3.1.0]hex-3-yl)-4-oxo-1,4-dihydro[1,8]naphtyridine-3-carboxylicacid;

JA 1005:

1-(2,4-difluorophenyl)-6-fluoro-7-((1R,5S)-6-{({4-fluoro[(4-nitrophenyl)-sulfonyl]anilino}carbothionyl)[(4-nitrophenyl)sulfonyl]amino}-3-azabicyclo[3.1.0]hex-3-yl)-4-oxo-1,4-dihydro[1,8]naphtyridine-3-carboxylicacid.

Furthermore, the present invention relates to a compound as set forthabove for use as a pharmaceutical.

Accordingly, the present invention also relates to a pharmaceuticalcomposition comprising a compound as set forth above as activeingredient in association with a pharmaceutically acceptable adjuvant,diluent or carrier.

Moreover, the present invention relates to an animal feed, foodconcentrate or drinking water comprising a compound as set forth above.

It should be noted that the composition and animal feed according to thepresent invention may optionally include two or more of the aboveoutlined compounds.

In addition, the present invention relates to the use of a compound asdefined above for the manufacture of a medicament for treatment ofbacterial and parasitic disorders, particularly coccidiosis anddisorders related thereto.

The present invention is also concerned with a method for treatment ofbacterial and parasitic disorders, particularly coccidiosis anddisorders related thereto, wherein said method comprises administeringto an animal, preferably poultry, of a therapeutically effective amountof a compound as defined above.

Although the present compounds were shown to be especially suitable fortreatment of coccidiodis (vide infra), it was anticipated that they arealso therapeutically efficient against other protozoa, such as those setforth below as non-limiting examples:

Tryanosoma, such as T. cruzi, T. brucei, T. congolense, T. evansi and T.simiae;

Toxoplasma, such as T. gondii;

Plasmodium;

Babesia spp.;

Theileria spp.;

Leishmania, such as L. tropica, L. major and L. donavani;

Entaamoeba histolytica;

Giardia intestinalis;

Hexamita meleagridis;

Trichomonas spp.

Trypanosoma spp. is the cause of sleeping sickness in humans andanimals, particularly in Africa. It is transmitted by the bite of thetsetse flies. It is well known that new compounds for treatment ofTrypanosoma infections are an ongoing demand in the art.

Consequently, the present compounds were evaluated against Trypanosomaas well, and it was shown that they are also highly efficient fortreatment of Trypanosoma parasites (vide infra).

Thus, the present invention also specifically relates to the use of thepresent compounds for the manufacture of a medicament for treatment ofparasitic infection caused by Trypanosoma.

Accordingly, the present invention is also specifically concerned with amethod for treatment of parasitic disorders caused by Trypanosoma,wherein said method comprises administering to an animal of atherapeutically effective amount of a compound as defined above.

The present compounds are also anticipated to be active againstarthropods or helminth parasites, such as flatworms and nematodes.Typical examples of such parasites are disclosed in U.S. Pat. No.5,863,775, the entire teachings of which are incorporated herein byreference.

The typical dosage of the compounds according to the present inventionvaries within a wide range and will depend on various factors such asthe particular requirement of each receiving individual and the route ofadministration. The dosage is generally within the range of 0.01-1000mg/kg animal feed or body weight.

The present invention is further illustrated by the followingnon-limiting experimental part.

Preparation of the Compounds of the Present Invention

General experimental information:

For thin liquid chromatography (TLC) monitoring of reactions, amethanol/benzene/NH₃(aq) 75:20:5 system was used. The products wererecrystallized in acetone or chloroform/methanol (50:50 or 75:25). NMRdata are given below as ¹H NMR (δ, ppm), unless otherwise provided.

JA 1 (C₂₃H₂₂FN₃O₃S):

Prepared essentially as JA 2 (vide infra), although an excess ofbenzenesulfonyl chloride was used instead of 4-toluenesulfonyl chloride(TsCl). JA 1 was obtained as a white powder in a yield of 90%. Compounddata:

Molecular Weight: 471.502; Composition: C(58.59%), H(4.70%), F(4.03%),N(8.91%), O(16.79%), S(6.80%) NMR: 14.41, 8.65, 7.86, 7.62, 7.29, 3.95,3.33, 3.19, 3.14, 1.17, 1.00.

JA 2 (C₂₄H₂₄FN₃O₅S):

In a round bottomed flask, ciprofloxacin (2 g, 6.04 mmol; see U.S. Pat.No. 4,670,444) was dissolved in dimethylformamide (DMF; 30 ml) followedby addition of pyridine (1.5 ml). An excess of TsCl was added, and thereaction mixture was heated for 5 h at 98° C. The excess of TsCl wasneutralized with 20% NaOH (w/v; aq), and the pH was adjusted to 7. Thesolvent was evaporated, and addition of cold water gave a precipitate,which was filtered and washed with cold methanol and then dried in anoven at 60° C., thereby giving JA 2 as an off-white powder (53.2%yield). Compound data;

Molecular Weight: 485.529; Composition: C(59.37%), H(4.98%), F(3.91%),N(8.65%), O(16.48%); NMR: 14.41 (s), 8.65 (s), 7.86 (d), 7.78 (d), 7.75(d), 7.47 (m), 7.35 (m), 3.95 (m), 3.40 (m), 2.40 (m), 1.22, 1.12, 1.03,1.17, 0.92.

JA 3 (C₂₃H₂₁FN₄O₇S):

Prepared in a manner essentially identical to that used for JA 2,although 4-nitrobenzenesulfonyl chloride (1.6 g, 7.22 mmol) was usedinstead of TsCl. JA 3 was obtained as a yellowish powder (94% yield).Compound data:

Molecular Weight: 516.5; Composition: C(53.48%), H(4.1%), F(3.68%),N(10.85%), O(21.68%), S(6.21%); NMR: 14.41, 8.65, 8.20, 7.93, 7.91,7.86, 7.78, 7.75, 3.95, 3.40, 3.33, 3.19, 3.14, 1.22, 1.14, 1.17, 1.03,1.00, 0.92.

JA 4 (C₂₄H₂₄FN₃O₆S)

Prepared essentially as JA 2, although 4-methoxybenzenesulfonyl chloride(2.3 g, 10 mmol) was used instead of TsCl. Compound data:

Molecular Weight: 501.528; Composition: C(57.48%), H(4.82%), F(3.79%),O(19.14%), S(6.39%); NMR: 14.41, 8.65, 7.86, 7.84, 7.58, 3.98, 3.84,1.17.

JA 5 (C₂₇H₂₄FN₃O₅s):

Prepared essentially as JA 2, although an excess of2-naphthalenesulfonyl chloride was used instead. JA 5 was obtained in88% yield as a white powder. Compound data:

Molecular Weight: 521.561; Composition: C(62.18%), H(4.64%), F(4.64%),N(8.06%), O(15.34%), S(6.15%) NMR: 14.41, 8.17, 7.86, 7.78, 7.40, 3.95,3.33, 3.19. 3.14, 1.17, 1.00.

JA 6 (C₂₆H₂₈FN₃O₅S)

Prepared essentially as JA 2, although an excess of mesitylsulfonylchloride was used instead of TsCl. JA 6 was obtained as an off-whitepowder (85% yield). Compound data:

Molecular Weight: 513.582; Composition: C(60.80%), H(5.5%), F(3.7%),N(88.18%), O(15.58%), S(6.24%); NMR: 14.41, 8.65, 7.86, 7.84, 7.78,6.68, 3.96, 1.01.

JA 7 (C₂₀H₂₄FN₃O₅S)

Prepared essentially as JA 2, but 1-propanesulfonyl chloride (5.64 ml,50.3 mmol) was used instead of TsCl. JA 7 was obtained as a white powder(90% yield). Compound data:

Molecular Weight: 437.486; Composition: C(54.91%), H(5.53%), F(4.34%),N(9.6%), O(18.29%), S(7.33); NMR: 14.40, 8.65, 7.86, 7.78, 3.95, 3.10,2.59, 1.96, 1.00, 0.99, 0.96.

JA 9 (C₂₄H₂₄FN₃O₅S):

Prepared essentially as JA 2, although phenylmethanesulfonyl chloride(1.4 g) was used instead of TsCl. JA 9 was obtained as an off-whitepowder (90% yield). Compound data:

Molecular Weight: 485.529; Composition: C(59.37%), H(4.98%), F(3.91%),N(8.65%), O(16.48%), S(6.6%); NMR: 14.41, 8.65, 7.78, 7.86, 7.50, 7.30,7.17, 4.17, 3.95, 3.20, 3.12, 1.17, 1.00.

JA 10 (C₁₈H₂₀FN₃O₅S):

Prepared essentially as JA 2. An excess of methanesulfonyl chloride wasused instead of TsCl. JA 10 was obtained in 95% yield as a creamypowder. Compound data:

Molecular Weight: 409.433; Composition: C(52.80%), H(4.92%), F(4.64%),N(10.26%), O(19.54%), S(7.83%); NMR: 14.41, 8.65, 7.86, 7.78, 3.95,3.13, 2.93, 1.17, 1.00.

JA 12 (C₁₈H₁₇F₄N₃O₅S)

Prepared essentially as JA 2, although an excess oftrifluoromethanesulfonyl chloride was used instead of TsCl. The requiredreaction time was 45 min in DMF. JA 12 was obtained as a white powder.Compound data:

Molecular Weight: 463.404; Composition: C(46.65%), H(3.7%), F(16.4%),N(9.07%), O(17.26%), S(6.92%); NMR: 14.41, 8.65, 7.86, 7.78, 3.95, 3.32,3.19, 3.14, 1.17, 1.00.

JA 13 (C₂₁H₁₉BrFN₃O₅S₂):

Prepared essentially as JA 2, although 5-bromothiophene-2-sulfonylchloride (1.6 g) was used instead of TsCl. The yield of JA 13 was 88%.Compound data:

Molecular Weight: 556.427; Composition: C(45.33%), H(3.44%), Br(14.36%),F(3.41%), N(7.55%), O(14.38%), S(11.53%); NMR: 14.41, 7.86, 7.78, 7.03,6.89, 3.95, 3.20, 1.17, 1.00.

JA 14 (C₂₃H₂₀Cl₂FN₃O₆S)

Prepared essentially as JA 2, although an excess of3,5-dichloro-2-hydroxybenzenesulfonyl chloride was used instead of TsCland the reaction required 24 h for completion. The yield of JA 14 was63%. Compound data:

Molecular Weight: 556.391; Composition: C(49.65%), H(3.62%), Cl(12.74%),F(3.41%), N(7.55%), O(17.25%), S(5.76%); NMR: 10.69, 8.65, 7.98, 7.86,7.78, 3.95, 3.33, 3.40, 3.19, 3.14, 1.17, 1.03, 1.00.

JA 20 (C₂₂H₂₁FN₄O₇S):

Prepared essentially as JA 2, although norfloxacin (2 g, 6.3 mmol; seeU.S. Pat. No. 4,146,719) was used instead of ciprofloxacin and4-nitrobenzenesulfonyl chloride (1.7 g) was used instead of TsCl as anelectrophilic reagent. JA 20 was obtained in 81% yield as a creamypowder. Compound data:

Molecular Weight: 504.489; Composition: C(52.38%), H(4.20%), F(3.77%),N(11.11%), O(22.20%), S(6.36%); NMR: 14.41, 8.93, 8.20, 7.93, 7.81,7.43, 4.55, 3.40, 3.33; 3.19, 3.14, 1.40.

JA 21 (C₂₃H₂₄FN₃O₆S)

Prepared essentially as JA 20, although the electrophilic reagent usedwas 4-methoxybenzenesulfonyl chloride (2 g, 9.7 mmol). JA 21 wasobtained as an off-white powder (96% yield). Compound data:

Molecular Weight: 489.518; Composition: C(56.43%), H(4.94%), F(3.88%),N(8.58%), O(19.61%), S(6.55%); NMR: 14.41, 8.93, 7.81, 7.56, 7.43, 6.85,4.55, 3.84, 3.40, 3.33, 3.19, 3.14, 1.40.

JA 26 (C₂₃H₂₄FN₃O₅S):

Prepared essentially as JA 20, although the electrophilic reagent usedwas phenylmethanesulfonyl chloride (1.8 g). JA 26 was obtained as acreamy powder (84% yield). Compound data:

Molecular Weight: 473.518; Composition: C(58.34%), H(5.11%), F(4.01%),N(8.87%), O(16.89%), S(6.77%); NMR: 14.41, 8.93, 7.81, 7.43, 7.31, 7.17,4.55, 4.17, 3.20, 3.12, 1.40.

JA 31 (C₂₃H₂₀Cl₂FN₃O₆S)

Prepared essentially as JA 20, although the electrophilic reagent usedwas 3,5-dichloro-2-hydroxybenzenesulfonyl chloride (2.5 g, 9.6 mmol). JA31 was obtained as a creamy powder (75% yield). Compound data:

Molecular Weight: 544.381; Composition: C(48.54%), H(3.70%), Cl(13.02%),F(3.49%), N(7.72%), O(17.63%), S(5.89%); NMR: 10.69; 8.93, 7.98, 7.81,7.43, 4.55, 3.40, 3.33, 3.19, 3.14, 1.40.

JA 39 (C₂₁H₁₉ClFN₅O₃)

2,6-dichloropyrazine (1 g, 6.7 mmol) was reacted with ciprofloxacin (2g, 6 mmol) using DMF (40 ml) as solvent in the presence of pyridine (1.5ml). The reaction mixture was refluxed at 123° C. for 5 h. Then icewater was added, and the precipitated powder product was washed withmethanol and dried. In an alternative approach, the DMF was removed invacuo using a rotary evaporator, followed by addition of ice water (50ml). The obtained precipitate was washed with cold water and methanol upto a point where no yellowish filtrate was observed. JA 39 was obtainedas a brown powder (90% yield). Compound data:

Molecular Weight: 443.859; Composition: C(S6.83%), H(4.31%), Cl(7.99%),F(4.28%), N(15.78%), O(10.81%); NMR: 14.41, 8.65, 8.06, 7.78, 7.54,3.95, 3.84, 3.32, 3.27, 1.17, 1.00.

JA 40 (C₂₂H₂₀BrFN₄O₃):

Prepared essentially as JA 39, but 2,5-dibromopyridine (1.43 g, 6.04mmol) was used instead of 2,6-dichloropyrazine. JA 40 was obtained in77% yield. Compound data:

Molecular Weight: 487.322; Composition: C(54.22%), H(4.14%), Br(16.40%),F(3.90%), N(11.50%), O(9.85%); NMR: 14.41, 8.65, 8.09, 7.78, 7.54, 7.24,6.43, 3.95, 3.84, 3.32, 3.27, 1.17, 1.00.

JA 42 (C₂₂H₂₀ClFN₄O₃)

Prepared essentially as JA 39, although 2,6-dichloropyridine (0.9 g,6.04 mmol) was used instead of 2,6-dichloropyrazine and the reactiontemperature was 120° C. JA 42 was obtained as a white powder (91%yield). Compound data:

Molecular Weight:.442.870; Composition: C(S9.66%), H(4.55%), Cl(8.01%),F(4.29%), N(12.65%), O(10.84%); NMR: 14.41, 8.65, 7.78, 7.54, 7.54,7.46, 7.01, 6.40, 3.95, 3.84, 3.32, 3.27, 1.17, 1.00.

JA 43 (C₂₁H₁₉ClFN₃O₅S₂):

Prepared essentially as JA 2, but 5-chlorothiophene-2-sulfonylchloride(1.31 g, 6.03 mmol) was used instead of TsCl. The reaction temperaturewas 110° C. and JA 43 was obtained as a white powder (77.6% yield).Compound data:

Molecular Weight: 511.976; Composition: C(49.26%), H(3.74%), Cl(6.92%),F(3.71%), N(8.21%), O(15.63%), S(12.53%) NMR: 14.41, 8.65, 7.86, 7.78,6.95, 6.82, 3.95, 3.20, 1.17, 1.00.

JA 46 (C₂₁H₂₀FN₅O₃)

Prepared essentially as JA 39, although 2-chloropyrazine was used aselectrophilic agent. JA 46 was obtained in 80% yield as a white powder.Compound data:

Molecular Weight: 409.414; Composition: C(61.61%), H(4.92%), F(4.64%),N(17.11), O(11.72%) NMR: 14.41, 8.65, 8.08, 7.84, 7.78, 7.54, 3.95,3.84, 3.32, 3.27, 1.17, 1.00

JA 61 (C₁₈H₁₃BrFN₃O₃):

Prepared essentially as JA 68 (vide infra), although 2 g of IM was used,and the nucleophilic reagent was 2-amino-5-bromopyridine (7 g). JA 61was obtained as a creamy powder (86% yield). Compound data:

Molecular Weight; 418.217; Composition: C(51.69%), H(3.13%), Br(19.11%),F(4.54%), N(10.05%), O(11.48%); NMR: 12.3, 8.65, 8.40, 8.18, 7.55, 7.15,6.71, 4.11, 1.17, 1.00.

JA 68 (C₁₉H₁₆FN₃O₃):

7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid (4 g, 14.2 mmol; hereinafter denoted “IM”) and 4-picolylamine (8 g)as nucleophilic reagent were refluxed overnight in DMF (50 ml) andpyridine (3 ml). After completion of the reaction, the solvents wereevaporated and cold water was added, whereby a precipitate was obtained.The precipitate was washed with water followed by methanol, after whichit was filtered and dried. JA 68 was obtained as a pale yellowish powder(73% yield) which was recrystallized from chloroform/acetone 70:30. ATLC spot of JA 68 displays fluorescence when exposed to UV light.Compound data:

Molecular Weight: 353.347;

Composition: C(64.58%), H(4.56%), F(S.38%), N(11.89%), O(13.58%); NMR:11.77, 8.70, 8.65, 8.08, 7.48, 6.41, 4.33, 4.11, 1.17, 1.00.

IM (C₁₃H₉ClFNO₃) was prepared as follows:

Condensation of 2,4-dichloro-5-fluoroacetophenone 2 with diethylcarbonate in the presence of NaH yielded ethyl2,4-dichloro-5-fluorobenzoylacetate 3. Treatment of the latter withtriethyl orthoformate in acetic anhydride gave the carbon homologue enolether intermediate 4 which was allowed to react with a slight excess ofcyclopropylamine in methylene chloride at room temperature to give theenaminoketoester 5. Cyclization of the latter with 1 molar equivalent ofNaH in refluxing dioxane yielded ethyl1,4-dihydro-4-oxo-quinoline-3-carboxylate 6 which was then hydrolysedwith aqueous NaOH to give1-cyclopropyl-6-chloro-7-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid (IM) 7. See also Scheme 1 below (Maurer, F. and Grohe, K., DE 3 435392 through Chem. Abst., Vol. 105, No.5, 1984, pp. 97158e). Compounddata:

Molecular Weight: 281.667; Composition: C(55.43%), H(3.22%), Cl(12.59%),F(6.74%), N(4.97%), O(17.04%); NMR (δ ppm; relative intensity):14.41;0.13, 8.65;6.37, 8.22;1.62, 4.11;2.3, 1.22;0.06, 1.12;0.14,1.03;0.14, 1.17;0.91, 1.00;0.90, 0.92;0.06.

JA 69 (C₂₀H₂₁FN₂O₅)

Prepared essentially as JA 68 (vide supra), although 2 g of IM was used,and the nucleophilic reagent was 4-aminocyclohexanecarboxylic acid (7g). JA 69 was obtained as a white powder (86% yield). Compound data:

Molecular Weight: 388.390; Composition: C(61.85%), H(5.45%), F(4.89%),N(7.21%), O(20.60%); NMR: 10.34, 8.65, 8.01, 6.31, 4.11, 3.29, 2.75,2.10, 1.77, 1.59, 1.17, 1.00.

JA 70 (C₂₁H₁₇FN₂O₅)

Prepared essentially as JA 68, although the amount of IM used was 5.11 gand the nucleophilic reagent was 4-(aminomethyl)benzoic acid (6 g). Thereaction temperature was 125° C. for 4 h, and JA 70 was obtained as acreamy powder (61.2% yield). Compound data:

Molecular Weight: 396.369; Composition: C(63.63%), H(4.32%), F(4.79%),N(7.07%), O(20.18%); NMR: 12.13, 8.65, 8.08, 7.87, 7.48, 6.41, 4.48,4.11, 1.17, 1.00.

JA 73 (C₁₈H₁₉FN₂O₄):

Prepared essentially as JA 68, although the amount of IM used was 8 g,the nucleophilic reagent was tetrahydrofurfurylamine (12.00 g), and thereaction temperature was 120° C. for 3 h. JA 73 was obtained as a whitepowder (75% yield). Compound data:

Molecular Weight: 346.353; NMR: 10.27, 8.65, 8.06,. 6.38, 4.11, 3.89,3.84, 2.98, 2.77, 1.11, 1.17, 1.00.

JA 74 (C₂OH₂₁FN₂O₅):

Prepared essentially as JA 68, although 2 g of IM was used, and thenucleophilic reagent was 4-isopropylaniline (2 g). JA 69 was obtained asa white powder (86% yield). Compound data:

Molecular Weight: 380.412; Composition: C(69.46%), H(5.56%), F(4.99%),N(7.36%), O(12.62%); NMR: 12.22, 8.65, 8.18, 7.20, 7.05, 4.11, 3.03,1.15, 1.20, 1.00.

JA 76 (C₂₀H₂₄FN₃O₃):

Prepared essentially as JA 68, although 2 g of IM was used, and thenucleophilic reagent was 2-(1-piperidinyl)-1-ethanamine (6 g). JA 76 wasobtained as a white powder (86% yield). Compound data:

Molecular Weight: 373.421; Composition: C(64.33%), H(6.48%), F(5.09%),N(11.25%), O(12.85%); NMR: 10.30, 8.65, 7.94, 6.34, 4.11, 3.21, 2.80,2.47, 2.40, 1.58, 1.48, 1.17, 1.03, 1.00.

JA 91 (C₂₅H₂₀FN₃O₅S):

Prepared exactly as JA 2 (vide supra), although instead JA 68 (0.8 g,2.27 mmol) was reacted with benzenesulfonyl chloride (3 g). JA 91 wasobtained in 52% yield. Compound data:

Molecular Weight: 493.508; Composition: C(60.84%), H(4.08%), F(3.85%),O(16.21%), S(6.50%); NMR: 14.41, 9.01, 8.65, 8.27, 7.81, 7.67, 7.42,7.08, 4.64, 4.11, 1.17, 1.00.

JA 103 (C₁₆H₁₈FN₃O₃):

Prepared essentially as JA 68, although 3 g of IM was used, and thenucleophilic reagent was ethylenediamine (3.5 g). When the reaction wascomplete, the solvent was removed in vacuo and acetone (30 ml) was addedto the residue. It should be noted that methanol should not be used atall here. An excess of cold water was subsequently added to obtain JA103 as a suspended powder, which was filtered, dried and recrystallized.JA 103 was obtained as a white powder (84% yield). Compound data:

Molecular Weight: 319.331; Composition: C(60.18%), H(5.68%), F(5.95%),N(13.16%), O(15.03%); NMR: 8.65, 7.97, 6.26, 6.12, 4.11, 3.31, 2.26,1.17, 1.00.

JA 105 (C₁₉H₂₂FN₃O₃):

Prepared exactly as JA 103, although 3 g of IM was used, and thenucleophilic reagent was 1,2-diaminocyclohexane (6 g). JA 105 wasobtained as a brownish powder (81% yield). Compound data:

Molecular Weight: 359.395; Composition: C(63.50%), H(6.17%), P(5.29%),N(11.69%), O(13.36%); NMR: 8.65, 8.01, 6.31, 5.32, 4.11, 2.83, 2.58,1.92, 1.46, 1.17, 1.00.

JA 117 (C₂₄H₂₂FN₃O₈S):

Prepared essentially as JA 2 (vide supra), although instead4-nitrobenzenesulfonyl chloride (0.8 g) was used as electrophile. JA 117was obtained as a white powder (76% yield). Compound data:

Molecular Weight: 531.511; Composition: C(54.23%), H(4.17%), F(3.57%),N(7.91%), O(24.08%), S(6.03%); NMR: 14.41, 8.65, 8.31, 8.12, 7.05, 4.11,3.89, 3.75, 3.67, 1.17, 1.00.

JA 135 (C₂₅H₂₅FN₂O₇S):

Prepared essentially as JA 2, although1-cyclopropyl-6-fluoro-4-oxo-7-[(tetrahydro-2-furanylmethyl)amino]-1,4-dihydro-3-quinolinecarboxylicacid and an excess of 4-methoxybenzenesulfonyl chloride were usedinstead. JA 135 was obtained in 86% yield as a white powder. Compounddata:

Molecular Weight: 516.540; Composition: C(58.13%), H(4.68%), F(3.68%),N(5.42%), O(21.68%), S(6.21%); NMR: 14.41, 8.65, 8.24, 7.75, 7.05, 6.96,4.11, 3.84, 3.89, 3.75, 3.67, 1.17, 1.00.

JA 136 (C₂₈H₂₅FN₂O₆S):

Prepared essentially as JA 2, although1-cyclopropyl-6-fluoro-4-oxo-7-[(tetrahydro-2-furanylmethyl)amino]-1,4-dihydro-3-quinolinecarboxylicacid and an excess of 2-naphthalenesulfonyl chloride were used instead.JA 136 was obtained in 86% yield as a white powder. Compound data:

Molecular Weight: 536.572; Composition: C(62.68%), H(4.70%), F(3.54%),N(5.22%), O(17.89%), S(5.98%); NMR: 14.41, 8.65, 8.24, 8.00, 7.76, 7.40,7.05, 4.11, 3.89, 3.67, 3.75, 1.17, 1.00.

JA 137 (C₂₆H₂₇FN₂O₆S):

Prepared essentially as JA 2, although1-cyclopropyl-6-fluoro-4-oxo-7-[(tetrahydro-2-furanylmethyl)amino]-1,4-dihydro-3-quinolinecarboxylicacid and an excess of 2-phenyl-1-ethanesulfonyl chloride were usedinstead. JA 137 was obtained in 86% yield as a white powder. Compounddata:

Molecular Weight: 514.567; Composition: C(60.69%), H(5.29%), F(3.69%),N(5.44%), O(18.66%), S(6.23%); NMR: 14.41, 8.65, 8.17, 7.39, 7.30, 6.92,4.11, 3.79, 3.68, 2.85, 1.17, 1.00.

JA 138 (C₁₉H₁₈F₄N₂O₆S):

Prepared essentially as JA 144 (vide infra), althoughtrifluoromethanesulfonyl chloride (0.6 g) was used as electrophile. JA138 was obtained as a creamy powder (70% yield). Compound data:

Molecular Weight: 478.416; Composition: C(47.70%), H(3.79%), F(15.88%),N(5.88%), N(5.86%), O(20.07%), S(6.70%); NMR: 14.41, 8.65, 8.07, 7.31,4.11, 3.99, 3.75, 3.61, 1.17, 1.00.

JA 139 (C₂₄H₂₃FN₂O₆S)

Prepared essentially as JA 117, although benzenesulfonyl chloride (0.7g) was used as electrophile. JA 139 was obtained in 76% yield. Compounddata;

Molecular Weight: 486.514; Composition; C(59.25%), H(4.77%), F(3.91%),N(S.76%), O(19.73%), S(6.59%); NMR: 14.41, 8.65, 8.24, 7.79, 7.42, 7.05,4.11, 3.89, 3.75, 1.17, 1.00.

JA 141 (C₂₂H₂₀ClFN₄O₄):

Prepared essentially as JA 39, although1-cyclopropyl-6-fluoro-4-oxo-7-[(tetrahydro-2-furanylmethyl)amino]-1,4-dihydro-3-quinolinecarboxylicacid (5.6 mmol) was used instead of ciprofloxacin. JA 141 was obtainedin 78% yield as a brownish powder. Compound data:

Molecular Weight: 458.870; Composition: C(57.58%), H(4.39%), Cl(7.73%),F(4.14%), N(12.21), O(13.95%); NMR: 14.41, 8.65, 8.15, 7.81, 4.57, 4.38,4.11, 4.03, 3.89, 3.81, 1.17, 1.00.

JA 142 (C₂₃H₂₁BrFN₃O₄):

Prepared essentially as JA 141, although instead 2,5-dibromopyridine(2.85 g) was used as electrophile. JA 142 was obtained as a creamypowder (80% yield). Compound data:

Molecular Weight: 502.333; Composition: C(54.99%), H(4.21%), Br(15.91%),F(3.78%), N(8.37%), O(12.74%); NMR: 14.41, 8.65, 8.36, 8.18, 7.51, 6.36,4.59, 4.41, 4.11, 4.03, 3.89, 3.81, 1.17, 1.00.

JA 143 (C₂₃H₂₁ClFN₃O₄):

Prepared essentially as JA 142, although 2,6-dichloropyridine (2.6 g)was used as electrophile. JA 143 was obtained as a creamy powder (72.3%yield). Compound data:

Molecular Weight: 457.882; Composition: C(60.33%), H(4.62%), Cl(7.74%),F(4.15%), N(9.18%), O(13.98%); NMR: 14.41, 8.65, 8.18, 7.72, 7.15, 6.33,4.59, 4.41, 4.11, 4.03, 3.89, 3.81, 1.17, 1.00.

JA 144 (C₂₂H₂₃FN₂O₆):

JA 73 (1 g, 2.9 mmol) was dissolved in DMF (40 ml), after whichacetoacetic ester (2.5 g; CAS #141979) was added. The reaction mixturewas refluxed for 3 h at 125° C., followed by solvent removal in vacuoand cold water addition to precipitate the product. Subsequentfiltration and recrystallization from acetone gave JA 144 as anoff-white powder (55% yield). Compound data:

Molecular Weight: 430.426; Composition: C(61.39%), H(5.39%), F(4.41%),N(6.51%), O(22.30%); NMR: 14.41, 8.65, 8.16, 7.25, 4.91, 4.53, 4.11,3.75, 3.53, 3.61, 1.9, 1.17, 1.00.

JA 145 (C₂₅H₂₆FN₃O₄)

Prepared essentially as JA 144, although 4-vinylpyridine (2 g) was usedas electrophile. JA 145 was obtained as a yellowish to off-white powder(62% yield). Compound data:

Molecular Weight: 451.490; Composition: C(66.51%), H(5.80%), F(4.21%),N(9.31%), O(14.17%); NMR: 14.41, 8.65, 8.48, 7.89, 7.55, 7.11, 3.95,3.81, 3.37, 3.19, 2.67, 1.18, 1.00.

JA 146 (C₂₅H₂₆FN₃O₄)

Prepared exactly as JA 145, although 2-vinylpyridine (2 g, 19 mmol) wasused as electrophile. JA 146 was obtained as a light brown powder (66%yield). Compound data:

Molecular Weight: 451.490; Composition: C(66.51%), H(5.80%), F(44.21%),N(9.31%), O(14.17%); NMR: 14.41, 8.65, 8.5, 7.89, 7.53, 7.49, 7.25,3.95, 3.81, 3.26, 2.83, 1.18, 1.00.

JA 156 (C₂₅H₁₉FN₄O₇S)

Prepared exactly as JA 91, although instead JA 68 (1 g) was reacted with4-nitrophenylsulfonyl chloride. JA 156 was obtained in 75% yield.Compound data:

Molecular Weight: 538.505; Composition: C(55.76%), H(3.56%), F(3.53%),N(10.40%), O(20.80%), S(5.95%); NMR: 14.41, 9.01, 8.65, 8.31, 8.14,7.67, 7.08, 4.64, 4.11, 1.17, 1.00.

JA 158 (C₂₄H₁₆BrFN4O₇S):

Prepared essentially as JA 2, although instead JA 61 (1 g, 2.4 mmol) wasreacted with 4-nitrobenzenesulfonyl chloride (2.7 g, 12.2 mmnol). JA 158was obtained as a creamy powder (67% yield). Compound data:

Molecular Weight: 603.375; Composition: C(47.77%), H(2.67%), Br(13.24%),F(3.15%), N(9.29%), O(18.56%), S(5.31%); NMR: 14.41, 8.65, 8.57, 8.35,8.16, 7.73, 7.48, 6.80, 4.11, 1.17, 1.00.

JA 159 (C₂₄H₁₆BrF₂N₃O₅S):

Prepared essentially as JA 2, although instead JA 61 (1 g, 2.4 mmol) wasreacted with 4-fluorobenzenesulfonyl chloride (2.5 g, 11.8 mmol), JA 159was obtained in a yield of 70%. Compound data:

Molecular Weight: 576.368; Composition: C(50.01%), H(2.80%), Br(13.86%),F(6.59%), N(7.29%), O(13.88%), S(5.56%); NMR: 14.41, 8.65, 8.57, 8.49,7.81, 7.73, 7.48, 6.80, 4.11, 1.17, 1.00.

JA 160 (C₁₉H₁₂BrF₄N₃O₅S)

Prepared exactly as JA 159, although instead JA 61 was reacted withtrifluoromethylsulfonyl chloride. JA 160 was obtained in a yield of 68%.Compound data:

Molecular Weight: 550.279; Composition: C(41.47%), H(2.20%), Br(14.52%),F(13.81%), N(7.64%), O(14.54%), S(5.83%); NMR: 14.41, 8.65, 8.40, 7.74,7.55, 7.06, 4.11, 1.17, 1.00.

JA 161 (C₂₈H₁₉BrFN₃O₅S)

Prepared exactly as JA 159, although instead JA 61 was reacted with2-naphtalenesulfonyl chloride. JA 161 was obtained in a yield of 66%.Compound data:

Molecular Weight: 608.436; Composition: C(55.27%), H(3.15%), Br(13.13%),F(3.12%), N(6.91%), O(13.15%), S(5.27%); NMR: 14.41, 8.57, 8.65, 8.04,7.74, 7.48, 7.40, 6.80, 4.11, 1.17, 1.00.

JA 162 (C₂₈H₂₅FN₂O₆S)

Prepared essentially as JA 2, although instead JA 73 (1 g, 2.9 mmol) wasreacted with 2-naphtalenesulfonyl chloride (3.27 g, 14.9 mmol). JA 162was obtained in a yield of 69%. Compound data:

Molecular Weight: 536.572; Composition: C(62.68%), H(4.70%), F(3.54%),N(5.22%), O(17.89%), S(5.98%); NMR: 14.41, 8.65, 8.24, 8.00, 7.76, 7.40,7.05, 4.11, 3.89, 3.75, 3.67, 1.17, 1.00.

JA 163 (C₂₉H₂₂FN₃O₅S)

Prepared essentially as JA 2, although instead JA 68 (1 g) was reactedwith 2-naphtalenesulfonyl chloride (3.2 g). JA 163 was obtained in ayield of 70%. Compound data:

Molecular Weight: 543.567; Composition: C(64.08%), H(4.08%), F(3.50%),N(7.73%), O(14.72%), S(5.90%); NMR: 14.41, 9.01, 8.65, 8.27, 8.02, 7.67,7.08, 4.64, 4.11, 1.17, 1.00.

JA 164 (C₂₀H₁₅F₄N₃O₅S):

Prepared exactly as JA 163, although instead JA 68 (1 g) was reactedwith trifluoromethanesulfonyl chloride (2.4 g, 14.2 mmol). JA 164 wasobtained in a yield of 72%. Compound data:

Molecular Weight: 485.410; Composition: C(49.49%), H(3.11%), F(15.66%),N(8.66%), O(16.48%), S(6.61%); NMR; 14.41, 9.01, 8.65, 8.09, 7.50, 7.33,4.59, 4.11, 1.17, 1.00.

JA 165 (C₂₄H₁₆ClFN₄O₃):

Prepared exactly as JA 163, although instead JA 68 (1 g) was reactedwith 2,6-dichloropyridine (2 g, 13.5 mmol). JA 165 was obtained in ayield of 75%. Compound data:

Molecular Weight: 464.876; Composition: C(62.01%), H(3.90%), Cl(7.63%),F(4.09%), N(12.05%), O(10.32%); NMR: 14.41, 8.72, 8.65, 8.20, 7.74,7.51, 7.15, 6.36, 5.56, 4.11, 1.17, 1.00.

JA 166 (C₂₃H₁₇ClFN₅O₃):

Prepared exactly as JA 163, although instead JA 68 (1 g, 2.83 mmol) wasreacted with dichloropyrazine (0.6 g, 4.0 mnol). JA 166 was obtained ina yield of 66%. Compound data:

Molecular Weight: 465.864; Composition: C(59.30%), H(3.68%), Cl(7.61%),F(4.08%), N(15.03%), O(10.30%); NMR: 14.41, 8.72, 8.65, 8.16, 7.84,7.60, 5.54, 4.11, 1.17, 1.00.

JA 167 (C₂₄H₁₈BrFN₄O₃):

Prepared exactly as JA 163, although instead JA 68 (1 g, 2.83 mmol) wasreacted with 2,5-dibromopyridine. JA 167 was obtained in a yield of 69%.Compound data:

Molecular Weight: 509.327; Composition: C(56.60%), H(3.56%), Br(15.69%),F(3.73%), N(11.00%), O(9.42%); NMR: 14.41, 8.72, 8.65, 8.38, 8.20, 7.51,6.37, 5.56, 4.11, 1.17, 1.00.

JA 168 (C₂₇H₂₀FN₃O₉S):

Prepared exactly as JA 2, although instead 4-nitrobenzenesulfonylchloride (2.2 g) was used as 30 electrophile and reacted with JA 70 (1.0g). JA 168 was obtained as a creamy powder (72% yield). Compound data:

Molecular Weight: 581.527; Composition: C(55.77%), H(3.47%), F(3.27%),N(7.23%), O(24.76%), S(5.51%); NMR: 13.63, 8.65, 8.31, 8.14, 8.18, 7.68,7.08, 4.67, 4.11, 1.17, 1.00.

JA 169 (C₃₁H₂₃FN₂O₇S):

Prepared essentially as JA 168, although instead JA 70 (1 g, 2.5 mmol)was reacted with 2-naphtalenesulfonyl chloride (2.3 g). JA 169 wasobtained as a white powder (70% yield). Compound data:

Molecular Weight: 586.588; Composition: C(63.47%), H(3.95%), F(3.24%),N(4.78%), O(19.09%), S(5.47%); NMR: 13.63, 8.65, 8.18, 7.68, 7.40, 7.08,4.67, 4.11, 1.17, 1.00.

JA 170 (C₂₂H₁₆F₄N₂O₇S)

Prepared exactly as JA 169, although instead trifluoromethanesulfonylchloride was used as the electrophilic reagent. JA 170 was obtained as awhite powder (70% yield). Compound data:

Molecular Weight: 528.431; Composition: C(50.00%), H(3.05%), F(14.38%),N(5.30%), O(21.19%), S(6.07%); NMR: 13.63, 8.65, 8.18, 7.51, 7.33, 4.62,4.11, 1.17, 1.00.

JA 171 (C₂₆H₁₉ClFN₃O₅):

Prepared exactly as JA 169, although instead 2,6-dichloropyridine (0.45g) was used as the electrophilic reagent. JA 171 was obtained in 68%yield. Compound data:

Molecular Weight: 507.897; Composition: C(61.48%), H(3.77%), Cl(6.98%),F(3.74%), N(8.27%), O(15.75%); NMR: 13.63, 8.65, 8.20, 7.89, 7.74, 7.53,7.15, 6.36, 5.59, 4.11, 1.17, 1.00.

JA 172 (C₂₅H₁₈ClFN₄O₅):

Prepared exactly as JA 169, although instead dichloropyrazine (0.45 9)was the electrophile used. JA 172 was obtained in 70% yield. Compounddata:

Molecular Weight: 508.885; Composition: C(59.00%), H(3.57%), Cl(6.97%),F(3.73%), N(11.01%), O(15.72%); NMR: 13.63, 8.65, 8.16, 7.89, 7.62,5.56, 4.11, 1.17, 1.00.

JA 173 (C₂₆H₁₉BrFN₃O₅):

Prepared exactly as JA 169, although instead 2,5-dibromopyridine (1 g)was the electrophile used. JA 173 was obtained in 77% yield. Compounddata:

Molecular Weight: 552.349; Composition: C(56.54%), H(3.47%), Br(14.47%),F(3.44%), N(7.61%), O(14.48%); NMR: 13.63, 8.65, 8.38, 7.89, 7.53, 6.37,5.59, 4.11, 1.17, 1.00.

B626 (C₂₇H₂₁F₂N₅O₅S):

In a round bottomed flask,6-fluoro-1-(4-fluorophenyl)-4-oxo-7-(1-piperazinyl)-1,4-dihydro-3-quinolinecarboxylicacid (5.56 mmol) was dissolved in a 10% aqueous solution of KOH (7.5ml), followed by addition of distilled water (10 ml) in order to obtaina clear solution. A solution of 4-nitrophenylisothiocyanate (1.02 g,5.56 mmol) in acetone (30 ml) was then added to the clear solution. Thereaction mixture was refluxed for 0.5 h, after which distilled water wasadded and the pH was adjusted to 7 by using HCl (2N). The resultingprecipitate was filtered off, washed with water and recrystallized fromchloroform/acetone 70:30. The yield of B626 was 91%. Compound data:

Molecular Weight: 565.549; Composition: C(57.34%), H(3.74%), F(6.72%),N(12.38%), O(14.15%), S(5.67%); NMR: 12.11, 8.74, 8.04, 7.95, 7.63,7.16, 6.91, 6.73, 3.34, 3.35, 2.56, 2.60.

B627 (C₂₄H₂₁ClFN₅O₅S):

Prepared exactly as B626, although7-(3-amino-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid (5.56 mmol) was used instead. The yield of B627 was 96%. Compounddata:

Molecular Weight: 545.971; Composition: C(52.80%), H(3.88%), Cl(6.49%),F(3.48%), N(12.83%), O(14.65%), S(5.87%); NMR: 10.29, 8.71, 8.16, 8.09,6.97, 5.27, 3.99, 3.78, 3.66, 3.26, 2.00, 1.97, 1.53, 1.17, 1.03, 1.00.

B628 (C₂₃H₂₀F₃N₅O₅S):

Prepared exactly as B626, although6,8-difluoro-1-(2-fluoroethyl)-4-oxo-7-(1-piperazinyl)-1,4-dihydro-3-quinolinecarboxylicacid (5.56 mmol) was used instead. The yield of B628 was 90%. Compounddata:

Molecular Weight: 535.497; Composition: C(51.59%), H(3.76%), F(10.64%),N(13.08%), O(14.94%), S(5.99%); NMR: 12.04, 8.65, 8.04, 7.13, 6.92,4.11, 3.7, 3.63, 3.39, 3.29, 2.70, 2.62, 2.09, 1.18, 1.00.

B629 (C₂₆H₂₆FN₅O₅S):

Prepared exactly as B626, although1-cyclopropyl-6-fluoro-5-methyl-7-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid (5.56 mmol) was used instead. The yield of B629 was 91%. Compounddata:

Molecular Weight: 539.580; Composition: C(57.87%), H(4.86%), F(3.52%),N(12.98%), O(14.83%), S(5.94%); NMR: 12.04, 8.65, 8.04, 7.13, 6.92,4.11, 3.70, 3.63, 3.39, 3.29, 2.70, 2.62, 2.09, 1.18, 1.00.

B630 (C₂₄H₂₃F₂N₅O₅S):

Prepared exactly as B626, although1-ethyl-6,8-difluoro-7-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid.HCl (2 g, 5.15 mmol) was used instead. The yield of B630 was 93%.Compound data:

Molecular Weight: 531.533; Composition: C(54.23%), H(4.36%), F(7.15%),N(13.18%), O(15.05%), S(6.03%); NMR: 12.04, 9.02, 8.04, 7.85, 6.92,4.51, 3.66, 3.50, 3.43, 2.70, 2.60, 1.55, 1.19.

B631 (C₂₄H₂₂FN₅O₆S):

Prepared exactly as B626, although9-fluoro-3-methyl-7-oxo-10-(1-piperazinyl)-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylicacid (5.56 mmol) was used instead. The yield of B631 was 92%. Compounddata:

Molecular Weight: 527.526; Composition: C(54.64%), H(4.20%), F(3.60%),N(13.28%), O(18.20%), S(6.08%); NMR: 12.11, 8.93, 8.04, 7.35, 6.91,4.52, 4.49, 4.42, 3.43, 3.24, 2.95, 2.56, 2.60.

B632 (C₂₃H₂₀FN₅O₅S₂):

Prepared exactly as B626, although9-fluoro-7-oxo--(1-piperazinyl)-2,3-dihydro-7H-[1,4]thiazino[2,3,4-ij]quinoline-6-carboxylicacid (5.56 mmol) was used instead. The yield of B632 was 96%. Compounddata:

Molecular Weight: 529.566; Composition: C(52.16%), H(3.81%), F(3.59%),N(13.22%), O(15.11%), S(12.11%); NMR: 12.11, 8.93, 8.04, 7.35, 6.91,4.52, 4.49, 4.42, 3.43, 3.24, 2.95, 2.56, 2.60.

B633 (C₂₄H₂₂F₂N₆O₅S)

Prepared exactly as B626, although5-amino-1-cyclopropyl-6,8-difluoro-4-oxo-7-(1-piperazinyl)-1,4-dihydro-3-quinolinecarboxylicacid (5.56 mmol) having its 5-amino group acetyl-protected (by previousreaction with Ac₂O) was used instead. The yield of B633 was 96%.Compound data:

Molecular Weight: 544.532; Composition: C(52.94%), H(4.07%), F(6.98%),N(15.43%), O(14.69%), S(5.89%); NMR: 11.07, 8.84, 8.04, 6.91, 4.26,3.55, 3.49, 2.60, 2.56, 1.17, 1.00.

B634 (C₂₈H₂₂F₃N₅O₅S):

Prepared exactly as B626, although1-(2,4-difluorophenyl)-6-fluoro-7-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid (5.56 mmol) was used instead. The yield of B634 was 98%. Compounddata:

Molecular Weight: 597.566; Composition: C(56.28%), H(3.71%), F(9.54%),N(11.72%), O(13.39%), S(5.37%); NMR: 12.04, 8.93, 8.04, 7.59, 7.08,6.92, 6.79, 6.59, 3.69, 3.39, 3.32, 2.70, 2.60, 1.19.

B635 (C₃₄H₂₅F₃N₆O₉S₂):

Prepared exactly as JA 2, although1-(2,4-difluorophenyl)-6-fluoro-7-{3-methyl-4-[(4-nitroanilino)carbothioyl]-1-piperazinyl}-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid was reacted with 4-nitrobenzenesulfonyl chloride instead of TsCl.B635 was obtained as a creamy powder (92% yield). Compound data:

Molecular Weight: 782.725; Composition: C(52.17%), H(3.22%), F(7.28%),N(10.74%), O(18.40%), S(8.19%); NMR: 14.41, 8.93, 8.26, 7.64, 7.57,7.09, 6.79, 6.59, 3.53, 3.41, 3.23, 3.11, 2.49, 1.22.

B636 (C₂₄H₂₄F₂N₄O₃S)

Prepared essentially as B626, although1-ethyl-6,8-difluoro-7-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid.HCl (2.6 mmol) was instead reacted with phenylisothiocyanate (3mmol). B636 was obtained in 91% yield as a white powder. Compound data:

Molecular Weight: 486.535; Composition: C(59.25%), H(4.97%), F(7.81%),N(11.52%), O(9.87%), S(6.59%); NMR: 12.04, 9.02, 7.85, 7.61, 7.22, 4.51,3.66, 3.63, 3.50, 3.43, 3.24, 2.70, 2.61, 1.55, 1.19.

B637 (C₂₄H₂₂F₂N₄O₃S):

Prepared exactly as B626, although 4-fluorophenylisothiocyanate was usedinstead of 4-nitrophenylisothiocyanate. B637 was obtained in 91% yieldas a white powder. Compound data:

Molecular Weight: 484.519; Composition: C(59.49%), H(4.58%), F(7.84%),N(11.56%), O(9.91%), S(6.62%); NMR: 12.11, 8.65, 7.78, 7.70, 7.57, 7.14,3.95, 3.43, 3.35, 2.56, 2.6, 1.17, 1.00.

B638 (C₂₃H₂₂FN₅O₅S):

Prepared exactly as B626, although1-ethyl-6-fluoro-4-oxo-7-(1-piperazinyl)-1,4-dihydro-3-quinolinecarboxylicacid (5.56 mmol) was used instead. The yield of B638 was 93%. Compounddata:

Molecular Weight: 499.516; Composition: C(55.30%), H(4.44%), F(3.80%),N(14.02%), O(16.01%), S(6.42%); NMR: 12.11, 8.93, 8.04, 7.81, 7.15,6.91, 4.55, 3.43, 3.37, 2.60, 2.56, 1.40.

JA 1000 (C₂₈M₁₈F₄N₄O₅S)

Prepared essentially as JA 2, although7-[(1R,5S)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylicacid (6.3 mmol; see U.S. Pat. No. 5,164,402) and 4-fluorobenzenesulfonylchloride (7 mmol) were used instead. JA 1000 was obtained in 82% yieldas a creamy powder. Compound data:

Molecular Weight: 574.505; Composition: C(54.36%), H(3.16%), F(13.23%),N(9.75%), O(13.92%), S(5.58%); NMR: 9.36, 8.88, 8.44, 7.64, 7.30, 6.92,6.72, 3.00, 2.80, 2.66, 0.96.

JA 1001 (C₂₅H₁₇ClF₃N₅O₃):

Prepared essentially as JA 42, although7-[(1R,5S)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylicacid (6.3 mmol) was used instead of ciprofloxacin. JA 1001 was obtainedin 90% yield as a creamy powder. Compound data:

Molecular Weight: 527.882; Composition: C(56.88%), H(3.25%), Cl(6.72%),F(10.80%), N(13.27%), O(9.09%); NMR: 8.88, 8.77, 8.44, 7.54, 7.08, 6.92,6.72, 6.30, 3.19, 2.85, 2.51, 1.14.

JA 1002 (c₂₄H₁₆ClF₃N₆O₃):

Prepared essentially as JA 39, although7-[(1R,5S)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]-1-(2,4-difluorophenl)-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylicacid (6.3 mmol) was used instead of ciprofloxacin. JA 1002 was obtainedin 90% yield as a brownish powder. Compound data:

Molecular Weight: 528.870; Composition: C(54.50%), H(3.05%), Cl(6.70%),F(10.78%), N(15.89%), O(9.08%); NMR: 9.44, 8.88, 8.44, 8.08, 7.82, 7.27,6.92, 6.72, 3.19, 2.72, 1.14.

JA 1003 (C₂₇H₁₉F₄N₆O₄):

Prepared exactly as B626, although7-[(1R,5S)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylicacid (5.6 mmol) and 4-fluorophenylthiocyanate (5.6 mmol) were usedinstead. JA 1003 was obtained in 90% yield as a creamy powder. Compounddata:

Molecular Weight: 527.882; Composition: C(58.59%), H(3.46%), F(13.73%),N(12.65%), O(11.56%); NMR: 9.06, 8.88, 8.44, 7.27, 7.06, 6.96, 6.72,3.08, 2.75, 1.64, 1.42.

JA 1004 (C₂₇H₁₉F₄N₅O₃S):

Prepared exactly as JA 1003, although 4-fluorophenylisothiocyanate (5.6mmol) was used instead of 4-fluorophenylthiocyanate. JA 1003 wasobtained in 90% yield as a creamy powder. Compound data:

Molecular Weight: 569.531; Composition: C(56.94%), H(3.36%), F(13.34%),N(12.30%), O(8.43%), S(5.63%); NMR: 9.73, 8.88, 8.44, 7.81, 7.27, 7.19,6.92, 6.72, 3.08, 2.73, 1.91, 1.48.

JA 1005 (C₃₉H₂₅F₄N₇O₁₁S₃):

Prepared essentially as JA 2, although1-(2,4-difluorophenyl)-6-fluoro-7-((1R,5S)-6-{[(4-fluoroanilino)carbothioyl]amino}-3-azabicyclo[3.1.0]hex-3-yl)-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylicacid (6.3 mmol; see U.S. Pat. No. 5,164,402) and an excess of4-fluorobenzenesulfonyl chloride were used instead. JA 1005 was obtainedin 79% yield as a creamy powder. Compound data:

Molecular Weight: 939.848; Composition: C(49.84%), H(2.68%), F(8.09%),N(10.43%), O(18.73%), S(10.24%); NMR: 14.41, 8.88, 8.44, 8.35, 7.49,7.27, 6.92, 6.72, 3.06, 2.76, 1.66.

JA 1006 (C₂₆H₂₆F₂N₄O₈S):

Prepared exactly as JA 1005, although7-[3-(aminomethyl)-3-(fluoromethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid (6 mmol; see U.S. Pat. No. 5,677,316) was used instead. JA 1006 wasobtained in 72% yield as a creamy powder. Compound data:

Molecular Weight: 592.570; Composition: C(52.70%), H(4.42%), F(6.41%),N(9.45%), O(21.60%), S(5.41%); NMR: 10.06, 8.61, 8.41, 7.83, 4.22, 4.09,4.02, 3.61, 3.45, 3.27, 2.90, 2.79, 2.69, 1.89, 1.83, 1.18, 1.00, 0.92.

JA 1007 (C₂₄H₂₄ClF₂N₆O₄):

Prepared essentially as JA 39, although7-[3-(aminomethyl)-3-(fluoromethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid (6.3 mmol) was used instead. JA 1007 was obtained in 88% yield as abrownish powder. Compound data:

Molecular Weight: 519.928; Composition: C(55.44%), H(4.65%), Cl(6.82%),F(7.31%), N(13.47%), O(12.31%); NMR: 9.32, 8.61, 8.08, 7.83, 4.15, 4.02,3.61, 3.43, 2.77, 1.90, 1.84, 1.22, 1.18, 1.00.

JA 1008 (C₂₅H₂₅ClF₂N₄O₄):

Prepared exactly as JA 1001, although7-[3-(aminomethyl)-3-(fluoromethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid (6.3 mmol) was used instead of ciprofloxacin. JA 1008 was obtainedin 86% yield as a brownish powder. Compound data:

Molecular Weight: 518.940; Composition: C(57.86%), H(4.86%), Cl(6.83%),F(7.32%), N(10.80%), O(12.33%); NMR: 9.67, 8.61, 7.83, 7.41, 7.07, 6.31,4.15, 4.02, 3.61, 3.43, 2.79, 1.90, 1.84, 1.22, 1.18, 1.00.

JA 1009 (C₂₇H₂₇F₃N₄O₄S):

Prepared exactly as JA 1004, although7-[3-(aminomethyl)-3-(fluoromethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid (6.3 mmol) was used instead. JA 1009 was obtained in 89% yield as abrownish powder. Compound data;

Molecular Weight: 560.589; Composition: C(57.85%), H(4.85%), F(10.17%),N(9.99%), O(11.42%), S(5.72%); NMR: 10.61, 8.61, 7.83, 7.19, 4.36, 4.22,4.18, 4.02, 3.61, 3.42, 3.34, 3.23, 2.79, 1.91, 1.85, 1.22, 1.18, 1.00,0.92.

JA 1010 (C₃₉H₃₃F₃N₆O₁₂S₃):

Prepared essentially as JA 2, although1-cyclopropyl-6-fluoro-7-[3-({[(4-fluoroanilino)carbothioyl]amino}-methyl)-3-(fluoromethyl)-1-pyrrolidinyl]-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid (6.3 mmol) and an excess of 4-nitrobenzenesulfonyl chloride wereused instead. JA 1010 was obtained in 82% yield as a creamy powder.Compound data:

Molecular Weight: 930.906; Composition: C(50.32%), H(3.57%), F(6.12%),N(9.03%), O(20.62%), S(10.33%); NMR: 14.41, 8.61, 8.46, 8.39, 7.83,7.64, 7.51, 4.43, 4.30, 4.12, 4.02, 3.61, 3.44, 3.26, 2.79, 1.88, 1.18,1.00.

JA 1012 (C₂₂H21ClFN₇O₄):

Prepared essentially as JA 39, although7-[3-(aminomethyl)-4-(methoxyimino)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylicacid (5.6 mmol) was used instead of ciprofloxacin. JA 1012 was obtainedin 78% yield as a brownish powder. Compound data:

Molecular Weight: 501.898; Composition: C(52.65%), H(4.22%), Cl(7.06%),F(3.79%), N(19.54%) , O(12.75%). NMR: 9.77, 8.58, 8.31, 8.08, 7.79,3.78, 3.64, 3.55, 3.11, 3.17, 1.18, 1.00.

JA 1013 (C₃₉H₃₆F₂N₈O₁₀S₃):

Prepared essentially as JA 2, although1-cyclopropyl-6-fluoro-7-[3-({[(4-fluoroanilino)carbothioyl]amino}-methyl)-4-(methoxyimino)-1-pyrrolidinyl]-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylicacid (5.7 mmol) and an excess of 4-methoxybenzenesulfonyl chloride wereused instead. JA 1010 was obtained in 68% yield as a creamy powder.Compound data:

Molecular Weight: 882.932; Composition: C(53.05%), H(4.11%), F(4.30%),N(9.52%), O(18.12%), S(10.90%) NMR: 14.41, 8.58, 8.24, 8.12, 7.64, 7.51,7.02, 4.74, 4.63, 3.84, 3.78, 3.64, 3.37, 3.15, 1.18, 1.00.

JAP 200 (C₂₂H₁₉Cl₂FN₄O₃):

Prepared essentially as JA 42, although7-(3-amino-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid (5.6 mmol) was used instead of ciprofloxacin. JAP 200 was obtainedin 88% yield as a creamy powder. Compound data:

Molecular Weight: 477.315; Composition: C(55.36%), H(4.01%), Cl(14.86%),F(3.98%), N(11.74%), O(10.06%); NMR: 10.79, 8.71, 8.16, 7.48, 7.02,6.30, 3.99, 3.81, 3.66, 3.22, 1.98, 1.56, 1.17, 1.00.

JAP 201 (C₂₈H₂₂Cl₂FN₅O₇S):

Prepared essentially as JA 2, although8-chloro-7-{3-[(6-chloro-2-pyridinyl)amino]-1-pyrrolidinyl}-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid (6.3 mmol) and an excess of 4-nitrobenzenesulfonyl chloride wereused instead. JAP 201 was obtained in 86% yield as a creamy powder.Compound data:

Molecular Weight: 662.474; Composition: C(50.76%), H(3.35%), F(2.87%),N(10.57%), O(16.91%), S(4.84%); NMR: 14.41, 8.71, 8.16, 7.96, 7.67,7.33, 6.63, 3.99, 3.8, 3.68, 3.29, 1.97, 1.53, 1.17, 1.00.

JAP 202 (C₂₇H₂₁Cl₂FN₆O₇S):

Prepared essentially as JA 2, although8-chloro-7-{3-[(6-chloro-2-pyridinyl)amino]-1-pyrrolidinyl}-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid (5.6 mmol) and an excess of 4-nitrobenzenesulfonyl chloride wereused instead. JAP 202 was obtained in 86% yield as a creamy powder.Compound data:

Molecular Weight: 663.462; Composition: C(48.88%), H(3.19%), Cl(10.69),F(2.86%), N(12.67%), O(16.88%), S(4.83%); NMR: 14.41, 8.74, 8.20, 7.93,7.16, 6.73, 3.40, 3.33, 3.19, 3.12.

JAP 203 (C₂₆H₂₀F₂N₄O₇S):

Prepared essentially as JA 2, although6-fluoro-1-(4-fluorophenyl)-4-oxo-7-(1-piperazinyl)-1,4-dihydro-3-quinolinecarboxylicacid (5.6 mmol; see U.S. Pat. No. 4,730,000) and an excess of4-nitrobenzenesulfonyl chloride were used instead. JAP 203 was obtainedin 84% yield as a creamy powder. Compound data:

Molecular Weight: 570.523; Composition: C(54.74%), H(3.53%), F(6.66%),N(9.82%), O(19.63%), S(5.62%); NMR: 14.41, 8.74, 8.20, 7.93, 7.16, 6.73,3.40, 3.33, 3.19, 3.12.

JAP 204 (C₂₅H₁₉ClF₂N₄O₃):

Prepared essentially as JA 42, although6-fluoro-1-(4-fluorophenyl)-4-oxo-7-(1-piperazinyl)-1,4-dihydro-3-quinolinecarboxylicacid (5.5 mmol) was used instead of ciprofloxacin. JAP 204 was obtainedin 90% yield as a creamy powder. Compound data:

Molecular Weight: 496.893; Composition: C(60.43%), H(3.85%), Cl(7.13%),F(7.65%), N(11.28%), O(9.66%); NMR: 14.41, 8.74, 7.95, 7.59, 7.46, 6.73,6.40, 3.90, 3.32.

JAP 205 (C₂₄H₁₈ClF₂N₅O₃):

Prepared essentially as JA 39, although6-fluoro-1-(4-fluorophenyl)-4-oxo-7-(1-piperazinyl)-1,4-dihydro-3-quinolinecarboxylicacid (5.6 mmol) was used instead. JAP 205 was obtained in 77% yield as abrownish powder. Compound data:

Molecular Weight: 497.881; Composition: C(57.90%), H(3.64%), Cl(7.12%),F(7.63%), N(14.07%), O(9.64%); NMR: 14.41, 8.74, 8.06, 7.95, 7.59, 7.16,6.73, 3.90, 3.32.

JAP 206 (C₂₂H₁₉F₃N₄O₇S):

Prepared essentially as JA 2, although6,8-difluoro-1-(2-fluoroethyl)-7-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid (5.6 mmol; see U.S. Pat. No. 4,398,029) and an excess of4-nitrobenzenesulfonyl chloride were used instead. JAP 206 was obtainedin 85% yield as a creamy powder. Compound data:

Molecular Weight: 540.470; Composition: C(48.89%), H(3.54%), F(10.55%),N(10.37%), O(20.72%), S(5.93%); NMR: 14.41, 9.66, 8.20, 7.93, 7.86,4.77, 4.66, 3.62, 3.54, 3.40, 3.16, 3.09.

JAP 207 (C₂₁H₁₈ClF₃N₄O₃):

Prepared essentially as JA 42, although6,8-difluoro-1-(2-fluoroethyl)-7-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid (5.6 mmol) was used instead. JAP 207 was obtained in 90% yield as acreamy powder. Compound data:

Molecular Weight: 466.841; Composition: C(54.03%), H(3.89%), Cl(7.59%),F(12.21%), N(12.00%), O(10.28%); NMR: 14.41, 9.66, 7.90, 7.46, 7.01,6.40, 4.77, 4.66, 3.90, 3.85, 3.62, 3.54, 3.44.

JAP 208 (C₂₀H₁₇ClF₃N₅O₃):

Prepared essentially as JA 39, although6,8-difluoro-1-(2-fluoroethyl)-7-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid (5.6 mmol) was used instead. JAP 208 was obtained in 77% yield as abrownish powder. Compound data:

Molecular Weight: 467.829; Composition: C(51.35%), H(3.66%), Cl(7.58%),F(12.18%), N(14.97%), O(10.26%); NMR: 14.41, 9.66, 8.06, 7.90, 4.77,4.66, 3.90, 3.62, 3.54, 3.44.

JAP 209 (C₂₅H₂₅FN₄O₇S):

Prepared essentially as JA 2, although1-cyclopropyl-6-fluoro-5-methyl-7-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid (5.6 mmol; see U.S. Pat. No. 4,920,120) and an excess of4-nitrobenzenesulfonyl chloride were used instead. JAP 209 was obtainedin 87% yield as a creamy powder. Compound data:

Molecular Weight: 544.553; Composition: C(55.14%), H(4.63%), F(3.49%),N(10.29%), O(20.57%), S(5.89%); NMR: 14.41, 8.65, 8.20, 7.90, 7.46,4.11, 3.46, 3.41, 3.17, 2.58, 2.09, 1.23, 1.17, 1.00.

JAP 210 (C₂₄H₂₄ClFN₄O₃):

Prepared essentially as JA 42, although1-cyclopropyl-6-fluoro-5-methyl-7-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid (5.6 mmol) was used instead of ciprofloxacin. JAP 210 was obtainedin 82% yield as a creamy powder. Compound data:

Molecular Weight: 470.924; Composition: C(61.21%), H(5.14%), Cl(7.53%),F(4.03%), N(11.90%), O(10.19%); NMR: 14.41, 8.65, 8.20, 7.90, 7.46,4.11, 3.46, 3.41, 3.17, 2.58, 2.09, 1.23, 1.17, 1.00.

JAP 211 (C₂₃H₂₃ClFN₅O₃):

Prepared essentially as JA 39, although1-cyclopropyl-6-fluoro-5-methyl-7-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid (5.6 mmol) was used instead. JAP 211 was obtained in 79% yield as abrownish powder. Compound data:

Molecular Weight: 467.829; Composition: C(58.54%), H(4.91%), Cl(7.51%),F(4.03%), N(14.84%), O(10.17%); NMR: 14.41, 8.65, 8.04, 7.13, 4.21,4.00, 4.11, 3.83, 3.24, 2.82, 2.09, 1.33, 1.17, 1.00.

JAP 213 (C₂₃H₂₂F₂N₄O₇S):

Prepared essentially as JA 2, although1-ethyl-6,8-difluoro-7-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid (5.6 mmol; see U.S. Pat. No. 4,528,287) and an excess of4-nitrobenzenesulfonyl chloride were used instead. JAP 213 was obtainedin 89% yield as a creamy powder. Compound data:

Molecular Weight: 536.506; Composition: C(51.49%), H(4.13%), F(7.08%),N(10.44%), O(20.88%), S(5.98%); NMR: 14.41, 9.02, 8.20, 7.90, 7.83,4.51, 3.46, 3.41, 3.14, 2.55, 1.55, 1.23.

JAP 214 (C₂₂H₂₁ClF₂N₄O₃):

Prepared essentially as JA 42, although1-ethyl-6,8-difluoro-7-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid (5.6 mmol) was used instead. JAP 210 was obtained in 85% yield as acreamy powder. Compound data:

Molecular Weight: 462.877; Composition: C(57.09%), H(4.57%), Cl(7.66%),F(8.21%), N(12.10%), O(10.37%); NMR: 14.41, 9.02, 7.85, 7.43, 7.02,6.38, 4.51, 4.20, 3.97, 3.40, 3.33, 3.22, 2.79, 1.55, 1.33.

JAP 215 (C₂₃H₂₁FN₄O₈S):

Prepared essentially as JA 2, although9-fluoro-3-methyl-7-oxo-10-(1-piperazinyl)-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylicacid (5.6 mmol; see U.S. Pat. No. 4,382,892) and an excess of4-nitrobenzenesulfonyl chloride were used instead. JAP 215 was obtainedin 89% yield as a creamy powder. Compound data:

Molecular Weight: 532.499; Composition: C(51.88%), H(3.97%), F(3.57%),N(10.52%), O(24.04%), S(6.02%); NMR: 14.41, 8.57, 7.99, 4.42, 3.82,3.53, 3.40, 3.33, 1.35.

JAP 216 (C₂₂H₂₀ClFN₄O₄):

Prepared essentially as JA 42, although9-fluoro-3-methyl-7-oxo-10-(1-piperazinyl)-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylicacid (5.6 mmol) was used instead. JAP 216 was obtained in 86% yield as acreamy powder. Compound data:

Molecular Weight: 458.870; Composition: C(57.58%), H(4.39%), Cl(7.73%),F(4.14%), N(12.21%), O(13.95%); NMR: 14.41, 8.57, 7.99, 7.46, 7.01,6.40, 4.42, 3.84, 3.53, 2.86, 1.35.

JAP 217 (C₂₁H₁₉ClFN₅O₄):

Prepared essentially as JA 39, although9-fluoro-3-methyl-7-oxo-10-(1-piperazinyl)-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylicacid (5.6 mmol) was used instead. JAP 217 was obtained in 80% yield as abrownish powder. Compound data:

Molecular Weight: 459.858; Composition: C(54.85%), H(4.16%), Cl(7.71%),F(4.13%), N(15.23%), O(13.92%); NMR: 14.41, 8.57, 8.06, 7.95, 4.42,3.82, 3.53, 2.86, 1.35.

JAP 218 (C₂₂H₁₉FN₄O₇S₂):

Prepared essentially as JA 2, although9-fluoro-7-oxo-10-(1-piperazinyl)-2,3-dihydro-7H-[1,4]thiazino[2,3,4-ij]quinoline-6-carboxylicacid (5.6 mmol; see U.S. Pat. No. 4,684,647) and an excess of4-nitrobenzenesulfonyl chloride were used instead. JAP 218 was obtainedin 89% yield as a creamy powder. Compound data:

Molecular Weight: 534.539; Composition: C(49.43%), H(3.58%), F(3.55%),N(10.48%), O(20.95%), S(12.00%); NMR: 14.41, 8.93, 8.20, 7.93, 7.35,4.49, .4.42, 3.40, 3.24, 2.95, 3.12.

JAP 219 (C21H₁₈ClFN₄O₃S):

Prepared essentially as JA 42, although9-fluoro-7-oxo-10-(1-piperazinyl)-2,3-dihydro-7H-[1,4]thiazino[2,3,4-ij]quinoline-6-carboxylicacid (5.6 mmol) was used instead. JAP 219 was obtained in 84% yield as acreamy powder. Compound data:

Molecular Weight: 460.910; Composition: C(54.72%), H(3.94%), Cl(7.6996),F(4.12%), N(12.12%), O(10.41%), S(6.96); NMR: 14.41, 8.93, 7.46, 7.35,7.01, 6.40, 4.49, 4.42 3.90, 3.24, 2.95.

JAP 220 (C₂₀H₁₇ClFN₅O₃S):

Prepared essentially as JA 39, although9-fluoro-7-oxo-10-(1-piperazinyl)-2,3-dihydro-7H-[1,4]thiazino[2,3,4-ij]quinoline-6-carboxylicacid (5.6 mmol) was used instead. JAP 220 was obtained in 76% yield as abrownish powder. Compound data:

Molecular Weight: 461.898; Composition: C(52.01%), H(3.71%), Cl(7.68%),F(4.11%), N(15.16), O(10.39%), S(6.94); NMR: 14.41, 8.93, 8.06, 7.35,4.49, 4.42, 3.90, 3.24, 2.95.

JAP 221 (C₂₉H₂₄F₂N₆O₁₁S₂):

Prepared essentially as JA 2, although5-amino-1-cyclopropyl-6,8-difluoro-4-oxo-7-(1-piperazinyl)-1,4-dihydro-3-quinolinecarboxylicacid (5.6 mmol; see U.S. Pat. No. 4,795,751) and an excess of4-nitrobenzenesulfonyl chloride were used instead. JAP 221 was obtainedin 83% yield as a creamy powder. Compound data:

Molecular Weight: 734.664; Composition: C(47.41%), H(3.29%), F(5.17%),N(11.44%), O(23.96%), S(8.73%); NMR: 14.92, 8.84, 8.20, 7.93, 4.26,3.40, 3.33, 3.16, 3.09, 1.17, 1.00.

JAP 222 (C₃₁H₂₈F₂N₆O₁₁S₂):

Prepared essentially as JA 2, although5-amino-1-cyclopropyl-7-(3,5-dimethyl-1-piperazinyl)-6,8-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid (5.6 mmol; see U.S. Pat. No. 4,795,751) and an excess of4-nitrobenzenesulfonyl chloride were used instead. JAP 222 was obtainedin 81% yield as a creamy powder. Compound data:

Molecular Weight: 762.717; Composition: C(48.82%), H(3.70%), F(4.98%),N(11.02%), O(23.07%), S(8.41%); NMR: 14.92, 8.84, 8.21, 7.87, 4.26,3.58, 3.00, 2.52, 1.23, 1.17, 1.00.

JAP 223 (C₂₉H₂₆Cl₂F₂N₆O₃):

Prepared essentially as JA 42, although5-amino-1-cyclopropyl-7-(3,5-dimethyl-1-piperazinyl)-6,8-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid (5.6 mmol) was used instead. JAP 223 was obtained in 80% yield as acreamy powder. Compound data:

Molecular Weight: 615.458; Composition: C(56.59%), H(4.26%), Cl(11.52%),F(6.17%), N(13.65%), O(7.80%); NMR: 14.52, 8.84, 7.79, 7.40, 7.09, 6.36,4.26, 3.88, 3.20, 2.77, 1.34, 1.17, 1.00.

JAP 224 (C₂₇H₂₄Cl₂F₂N₈O₃):

Prepared essentially as JA 39, although5-amino-1-cyclopropyl-7-(3,5-dimethyl-1-piperazinyl)-6,8-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid (5.6 mmol) was used instead. JAP 220 was obtained in 76% yield as abrownish powder. Compound data:

Molecular Weight: 617.434; Composition: C(52.52%), H(3.92%), Cl(11.48%),F(6.15%), N(18.15), O(7.77%); NMR: 15.62, 8.84, 8.36, 8.03, 4.26, 3.88,3.20, 2.77, 1.34, 1.17, 1.00.

JAP 225 (C27H₂₁F₃N₄O₇S):

Prepared essentially as JA 2, although1-(2,4-difluorophenyl)-6-fluoro-7-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid (5.6 mmol; see U.S. Pat. No. 4,730,000) and an excess of4-nitrobenzenesulfonyl chloride were used instead. JAP 225 was obtainedin 81% yield as a creamy powder. Compound data:

Molecular Weight: 602.540; Composition: C(53.82%), H(3.51%), F(9.46%),N(9.30%), O(18.59%), S(5.32%); NMR: 14.41, 8.93, 8.20, 8.06, 7.90, 7.08,6.79, 6.59, 3.48, 3.41, 3.17, 2.58, 1.23.

JAP 226 (C₂₅H₁₉ClF₃N₅O₃):

Prepared essentially as JA 39, although1-(2,4-difluorophenyl)-6-fluoro-7-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid (5.6 mmol) was used instead. JAP 226 was obtained in 78% yield as abrownish powder. Compound data:

Molecular Weight: 529.898; Composition: C(56.67%), H(3.61%), Cl(6.69%),F(10.76%), N(13.22), O(9.06%); NMR: 14.41, 8.93, 8.04, 7.59, 7.08, 6.79,6.59, 4.24, 4.00, 3.29, 2.82, 1.33.

JAP 227 (C26H₂₀ClF₃N₄O₃):

Prepared essentially as JA 42, although1-(2,4-difluorophenyl)-6-fluoro-7-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid (5.6 mmol) was used instead. JAP 227 was obtained in 83% yield as acreamy powder. Compound data:

Molecular Weight: 528.910; Composition: C(59.04%), H(3.81%), Cl(6.70%),F(10.78%), N(10.59%), O(9.07%); NMR: 14.41, 8.93, 8.05, 7.59, 7.43,7.02, 6.38, 4.24, 4.00, 3.29, 2.82, 1.33.

As for the preparation of the other compounds according to the presentinvention, useful general guidance is also provided by the followingpublications: EP 195 316 A1; U.S. Pat. Nos. 4,398,029; 4,528,287;4,684,647; 4,730,000; 4,795,751; 4,920,120; 5,164,402; 5,677,316;5,776,944; Org. Syntheses, Coll. Vol. 2, 586, pp. 1055-1057 (1943);ibid., 34-38, 179-183, 943-946; “Advanced Organic Chemistry”, March, J.,p.445 and pp. 802-803, 3^(rd) ed.

The synthesis of the required starting substances is readilyaccomplished by a person skilled in the art, should they not becommercially available. The additional compounds listed below were allprepared by using essentially the same synthetic protocol as that usedfor the previously disclosed compounds.

B700 (C₂₄H₂₂FN₅O₆):

1-cyclopropyl-6-fluoro-7-{4-[(4-nitroanilino)carbonyl]-1-piperazinyl}-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

B702 (C₂₄H₂₃F₂N₅O₆):

1-ethyl-6,8-difluoro-7-{3-methyl-4-[(4-nitroanilino)carbonyl]-1-piperazinyl}-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 41 (C₂₃H₂₁ClFN₃O₃S):

7-[4-(3-chloro-2-sulfanylphenyl)-1-piperazinyl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 47-2 (C₃₀H₂₁F₃N₄O₇S₂):

1-cyclopropyl-6-fluoro-7-[[(4-fluorophenyl)sulfonyl](6-{[(4-fluorophenyl)sulfonyl]amino}-2-pyridinyl)amino]-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 53-2 (C₃₀H₂₅F₃N₄)₅S₂):

1-cyclopropyl-6-fluoro-7-[4-({4-fluoro[(4-fluorophenyl)sulfonyl]anilino}carbothioyl)-1-piperazinyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 53-3 (C₃₀H₂₅F₂N₅O₇S₂):

1-cyclopropyl-6-fluoro-7-[4-({4-fluoro[(4-nitrophenyl)sulfonyl]anilino}carbothioyl)-1-piperazinyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 53-5 (C₂₈H₂₃ClF₂N₆O₃S):

7-(4-{[(6-chloro-2-pyrazinyl)-4-fluoroanilino]carbothioyl}-1-piperazinyl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid; JA 53-6 (C₂₉H₂₄ClF₂N₅O₃S):7-(4-{[(6-chloro-2-pyridinyl)-4-fluoroanilino]carbothioyl}-1-piperazinyl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 69-2 (C₂₄H₂₂ClFN₄O₅):

7-[(4-carboxycyclohexyl)(6-chloro-2-pyrazinyl)amino]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 69-3 (C₂₁H₂₀F₄N₂O₇S):

7-{(4-carboxycyclohexyl)[(trifluoromethyl)sulfonyl]-amino}-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 74-2 (C₂₁H₂₁FN₂O₃):

1-ethyl-6-fluoro-7-(4-isopropylanilino)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 76-2 (C₂₆H₂₇FN₄O₇S):

1-cyclopropyl-6-fluoro-7-{[(4-nitrophenyl)sulfonyl][2-(1-piperidinyl)ethyl]amino}-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 76-3 (C₂₄H₂₅ClFN₅O₃):

7-{(6-chloro-2-pyrazinyl)[2-(1-piperidinyl)ethyl]amino}-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 79-2 (C₂₉H₂₆F₃N₃O₇S₄):

1-cyclopropyl-6-fluoro-7-([(4-fluorophenyl)sulfonyl]{2-[(2-{[(4-fluorophenyl)sulfonyl]amino}ethyl)disulfanyl]-ethyl}amino)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 79-3 (C₂₉H₂₆FN₅O₁₁S₄):

1-cyclopropyl-6-fluoro-7-([(4-nitrophenyl)sulfonyl]{2-[(2{[(4-nitrophenyl)sulfonyl]amino}ethyl)disulfaryl]-ethyl}amino)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 82-2 (C₃₀H₂₈FN₅O₁₃S₂):

1-cyclopropyl-6-fluoro-7-([(4-nitrophenyl)sulfonyl]{2-[2-({[(4-nitrophenyl)sulfonyl]amino}methoxy)ethoxy]ethyl}-amino)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 82-3 (C₂₆H₂₄Cl₂FN₇O₅):

7-{(6-chloro-2-pyrazinyl)[2-(2-{[(6-chloro-2-pyrazinyl)amino]methoxy}ethoxy)ethyl]amino}-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 96-2 (C₃₈H₃₂F₂N6O₁₂S₂):

1-cyclopropyl-6-fluoro-7-[4-({({4-fluoro[(4-nitrophenyl)sulfonyl]anilino}carbonyl)[(4-nitrophenyl)sulfonyl]amino}methyl)-1-piperidinyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 97 (C₁₉H₂₂FN₃O₃):

1-cyclopropyl-6-fluoro-4-oxo-7-{[2-(1-pyrrolidinyl)ethyl]amino}-1,4-dihydro-3-quinolinecarboxylicacid;

JA 97-2 (C₂₆H₂₆FN₅O₅S):

1-cyclopropyl-6-fluoro-7-{[(4-nitroanilino)carbothioyl][2-(1-pyrrolidinyl)ethyl]amino}-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 97-3 (C₂₃H₂₃ClFN₅O₃):

7-{(6-chloro-2-pyrazinyl)[2-(1-pyrrolidinyl)ethyl]amino}-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 97-4 (C₂₅H₂₅FN₄O₇S):

1-cyclopropyl-6-fluoro-7-{([4-nitrophenyl)sulfonyl][2-(1-pyrrolidinyl)ethyl]amino}-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 97-5 (C₂₀H₂₁F₄N₃O₅S):

1-cyclopropyl-6-fluoro-4-oxo-7-{[2-(1-pyrrolidinyl)ethyl][(trifluoromethyl)sulfonyl]amino}-1,4-dihydro-3-quinolinecarboxylicacid;

JA 99-2 (C₃₃H₃₂F₃N₃O₇S₂):

1-cyclopropyl-6-fluoro-7-([(4-fluorophenyl)sulfonyl]{[3-({[(4-fluorophenyl)sulfonyl]amino}methyl)cyclohexyl]methyl}amino)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 102 (C₂₀H₂₇FN₄O₃):

7-({3-[(3-aminopropyl)(methyl)amino]propyl}amino)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 103-2 (C₁₈H₁₆F₇N₃O₇S₂):

1-cyclopropyl-6-fluoro-4-oxo-7-[[(trifluoromethyl)sulfonyl](3-{[(trifluoromethyl)sulfonyl]amino}propyl)amino]-1,4-dihydro-3-quinolinecarboxylicacid;

JA 103-3 (C₂₈H₂₄FN₅O₁₁S₂):

1-cyclopropyl-6-fluoro-7-[[(4-nitrophenyl)sulfonyl](3-{[(4-nitrophenyl)sulfonyl]amino}propyl)amino]-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 104-2 (C₂₁H₂₅F₄N₃O₅S):

1-cyclopropyl-7-{[3-(dimethylamino)-2,2-dimethylpropyl][(trifluoromethyl)sulfonyl]amino}-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 104-3 (C₂₅H₂₈FN₃O₄S):

1-cyclopropyl-7-[(3-(dimethylamino)-2,2-dimethylptopyl]-(2-thienylcarbonyl)aminol-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 106-3 (C₁₇H₁₄F₇N₃O₇S₂):

1-cyclopropyl-6-fluoro-4-oxo-7-[[(trifluoromethyl)sulfonyl](2-{[(trifluoromethyl)sulfonyl]amino}ethyl)amino]-1,4-dihydro-3-quinolinecarboxylicacid;

JA 106-4 (C₂₇H₂₂FN₅O₁₁S₂):

1-cyclopropyl-6-fluoro-7-[[(4-nitrophenyl)sulfonyl](2-{[(4-nitrophenyl)sulfonyl]amino}ethyl)amino]-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 107-2 (C₂₀H₂₀F₇N₃O₇S₂):

1-cyclopropyl-7-{(2,2-dimethyl-3-{[(trifluoromethyl)sulfonyl]amino}propyl)[(trifluoromethyl)sulfonyl]amino}-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 110 (C₂₈H₂₇FN₄O₃S):

7-(4-{[(anilinocarbothioyl)amino]methyl}-1-piperidinyl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 124 (C₂₃H₁₇FN₂O₅S):

1-cyclopropyl-6-fluoro-7[(2-furylmethyl)(2-thienylcarbonyl)amino]-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 128 (C₂₅H₂₆FN₃O₄S):

1-cyclopropyl-6-fluoro-4-oxo-7-[[2-(1-piperidinyl)ethyl]-(2-thienylcarbonyl)amino]-1,4-dihydro-3-quinolinecarboxylicacid;

JA 140 (C₂₃H₂₁FN₂O₅S):

1-cyclopropyl-6-fluoro-4-oxo-7-[(tetrahydro-2-furanylmethyl)(2-thienylcarbonyl)amino]-1,4-dihydro-3-quinolinecarboxylicacid;

JA 148 (C₂₁H₂₃FN₂O₆):

7-[acetoacetyl(2-methoxy-1-methylethyl)amino]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid;

JA 149 (C₂₃H₂₂FN₃O₈S):

1-cyclopropyl-6-fluoro-7-{(2-methoxy-1-methylethyl)[(4-nitrophenyl)sulfonyl]amino}-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid.

Biological Evaluation of the Present Compounds

Antibacterial Testing Against Gram-positive and Gram-negative Bacteria:

The antibacterial activity of the present compounds was investigated byin vitro evaluation of their M.I.C. (Minimum Inhibitory Concentration)values. The evaluation was conducted in complete accordance with the“Broth dilution method”, as outlined by the U.S. National Committee forClinical Laboratory Standards “NCCLS 1988”.

Solutions of the present compounds were prepared by dissolving 0.01 g ofa test compound in either 10% KOH (aq) or a 10% KOH/DMF mixture, afterwhich sterile, distilled H₂O was added up to a total volume of 10 ml,thereby yielding a test compound concentration of 1 000 μg/ml. Thevolume (ml) used of 10% KOH and DMF for dissolution of each respectivetest compound is given in Table 1 below.

In this evaluation, the antibacterial activity of the present compoundsand enrofloxacin as reference compound was tested against seven strainsof gram-positive bacteria, namely Bacillus subtilus (ATCC 6633),Bacillus cereus, Streptococcus faecium, Micrococcus Luteus (ATCC 9341),Staph. aureus (ATCC 29737), Staph. epidermidis (ATCC 12228) andStaphylococcus (ATCC 6538). The results are presented in the followingTable 6.

TABLE 6 M.I.C. values for compounds tested Compound KOH/DMF BacillusBacillus Streptoc. Microc. Staph. Staph. Staph. tested (ml) subtiluscereus faecium Luteus aureus epidermidis (ATCC 6538) Enrofloxacin0.10/0.10 0.500 0.250 1.000 2.000 0.250 0.120 0.120 JA 1  0.14/1.500.060 0.060 0.500 0.500 0.120 0.060 0.060 JA 2  0.10/0.70 0.120 0.0600.500 0.500 0.120 0.060 0.030 JA 3  0.10/—   0.060 0.060 0.250 1.0000.060 0.010 0.060 JA 4  0.10/0.10 0.010 0.010 0.060 0.250 0.060 0.0300.010 JA 5  0.10/0.50 0.008 0.030 0.120 0.500 0.060 0.010 0.060 JA 9 0.14/0.50 0.250 0.250 1.000 1.000 ≧0.120 0.120 0.060 JA 10  0.10/—  0.500 0.120 1.000 2.000 0.250 0.250 0.250 JA 12  0.10/0.50 0.120 0.0601.000 0.500 0.120 0.120 0.030 JA 21  0.10/—   0.250 0.010 0.500 2.0000.250 0.060 0.060 JA 39  0.10/0.50 0.060 0.010 0.250 1.000 0.120 0.0100.030 JA 40  0.12/1.00 0.120 0.060 1.000 2.000 0.250 0.120 0.060 JA 41 0.16/1.70 0.500 0.250 1.000 2.000 0.250 0.250 0.250 JA 42  0.10/1.700.010 0.060 0.250 1.000 0.030 0.008 0.060 JA 43  0.10/1.00 0.250 0.1201.000 1.000 0.120 0.250 0.030 JA 46  0.14/1.00 0.120 0.060 0.500 1.0000.120 0.120 0.120 JA 68  0.10/1.00 0.120 0.060 1.000 2.000 0.120 0.2500.120 JA 69  0.16/1.00 0.120 0.060 2.000 2.000 0.120 0.120 0.120 JA 70 0.10/0.50 0.250 0.120 2.000 1.000 0.120 0.250 0.120 JA 73  0.16/1.000.120 0.060 0.500 2.000 0.120 0.120 0.060 JA 74  0.14/1.00 0.120 0.1202.000 2.000 0.120 0.120 0.120 JA 76  0.10/1.00 0.120 0.120 1.000 2.0000.120 0.120 0.060 JA 102 0.14/1.00 0.120 0.060 1.000 2.000 0.060 0.1200.120 JA 124 0.10/1.00 0.120 0.120 1.000 2.000 0.120 0.120 0.120 JA 1280.10/1.20 0.120 0.060 1.000 2.000 0.120 0.060 0.120 JA 135 0.14/1.500.120 0.060 0.500 2.000 0.120 0.120 0.120 JA 136 0.10/1.50 0.120 0.0600.500 2.000 0.120 0.120 0.120 JA 137 0.10/0.10 0.120 0.250 1.000 2.0000.500 0.250 0.120 JA 138 0.10/1.00 0.120 0.060 1.000 2.000 0.250 0.1200.120 JA 140 0.10/1.00 0.060 0.060 0.500 1.000 0.120 0.120 0.060 JA 1410.10/—   0.120 0.120 1.000 2.000 0.250 0.120 0.120 JA 143 0.10/0.100.120 0.120 1.000 >2.000 0.250 0.120 0.120 JA 144 0.10/1.00 0.120 0.1200.500 1.000 0.120 0.120 0.060 JA 145 0.16/1.30 0.120 0.120 1.000 2.0000.120 0.120 0.120 JA 146 0.10/1.00 0.120 0.120 1.000 2.000 0.120 0.1200.120 JA 148 0.10/0.50 0.120 0.060 1.000 2.000 0.120 0.120 0.120 JA 1490.10/0.50 0.120 0.120 2.000 2.000 0.120 0.120 0.120

As is evident from Table 6 above, the compounds according to the presentinvention have excellent antibacterial properties. Indeed, theantibacterial activity of the present compounds against gram-positive Sbacteria is at least equal, and in some instances even clearly superior(e.g. JA 4 and JA 39), to that of enrofloxacin.

In the same manner as above, the M.I.C. values of the present compoundsJA 3, JA 5, JA 12, JA 42, JA 73 and enrofloxacin as reference compoundwere investigated also on gram-negative bacteria. The gram-negativebacteria used were E. coli (ATCC 25922), E. Coli (ATCC 8739), E. Coli(ATCC 10536), E. Coli Pathogenic, KL. Pnemonia (ATCC 10031), Bordetellabronchiseptic (ATCC 4617), Salmonella typhi, Salmonella spp., Proteusspp., Pasterulla Duck and Pasterulla Camel. In summary, it was foundthat all of said present compounds have antibacterial activity againstgram-negative bacteria, and that their activity is roughly equal to thatof enrofloxacin.

Antibacterial Testing Against Mycoplasma:

As is well known, Mycoplasma are bacteria which often cause severerespiratory tract infections in both humans and animals. As typicalexamples, an infection of M. pneumoniae in humans causes pneumonia,whereas an infection of M. gallisepticum in avians, especially chickens,normally causes chronic respiratory disease or sinusitis.

The M.I.C. values of the compounds JA 1, JA 3, JA 5,

JA 12, JA 42 and JA 43 were determined in vitro against M.gallisepticum. Enrofloxacin, tylosin and oxytetracyclin were used asreference compounds. The tested compounds were all stored and applied assolutions in distilled water. The M.I.C. evaluation was performed inmicrotitre plates, and the methodology employed was basically that ofTanner and Wu (Avian Disease, 36:714-717 (1992)). The results arepresented in Table 7 below:

TABLE 7 M.I.C. values against M. gallisepticum Compound tested M.I.C.values JA 1 0.03 JA 3 0.06 JA 5 0.12 JA 12 0.12 JA 42 0.25 JA 43 0.25Enrofloxacin 0.06 Tylosin 0.06 Oxytetracyclin 0.12

As can be seen in Table 7, the present compounds have antibacterialactivity against M. gallisepticum as well, and the high antibacterialactivity of JA 1 is noteworthy.

Antiparasitic Testing Against Coccidia:

The anticoccidial activity of the present compounds as prophylacticagents was evaluated in vivo on 60 one day old (1 day after hatch)chickens of Habbared X breed. The chickens were divided into four groupsof 20 birds each, and each group was located in a separate pen (1 m×1m). The chickens were then fed with unmedicated food up to day 7 afterhatch. Fresh water was supplied ad libitum .

On day 8 after hatch, the four groups were fed as follows (1 ppm=1 mgdrug/kg feed):

-   -   Group #1: feed containing JA 39 (100 ppm);    -   Group #2: feed containing JA 42 (100 ppm);    -   Group #3: feed containing Coxistac (60 ppm), a known        anticoccidial agent (see U.S. Pat. No. 3,857,948);

Group #4: feed containing no drug (control group).

The chickens were fed as above on day 8 and 9 after hatch. On day 10after hatch, each chicken was infected orally by 6 000-7 000 oocystscontaining a mixture of 5 mature sporulated strains, namely Eimeriaacervulina, E. maxima, E. necatrix, E. tenella and E. brunetti. Thegroups #1-3 received drug as above from day 10 to 21 after hatch.

From day 14 to 21 after hatch, fresh fecal droplets were collected andexamined daily. The average number of oocysts/g faeces was thencalculated in accordance with the so-called Mc-Master technique(Soulsby, E. J., Helminths, Arthropods & Protozoa of domesticatedanimals, p. 789, 6^(th) Ed., Williams & Wilkins Co. Baltimore (USA),Tindall & Cassell Ltd., London, 1968). The final weight of and meantotal amount of feed consumed by each bird were also examined, and theresults are summarized in Table 8 hereinbelow.

TABLE 8 Anticoccidial effect of JA 39 and JA 42 on chicken Averagenumber of Eimeria spp. oocysts/g faeces Mean amount Group Day afterhatch Mean body of feed (drug) 14 15 16 17 18 19 21 Total weight (g)consumed (g) #1 0.0 4000 5000 3000 0.0 0.0 0.0 12000 68.2 81 (JA 39) #20.0 4000 6000 3000 0.0 0.0 0.0 13000 73.7 91 (JA 42) #3 0.0 3000 40007000  2000 2000 0.0 18000 62.0 120 (Coxistac) #4 0.0 15000 24000 1.3 ×10⁶ 174000 0.0 0.0 1.4 × 10⁶ 57.3 120 (no drug)

As is evident from Table 8 above, the compounds

JA 39 and JA 42 have excellent anticoccidial effect. This is alsomanifested in the higher mean body weight and lower amount of feedconsumed as compared to both the Coxistac and the non-treated group.

Moreover, the prophylactic anticoccidial effect of

JA 12, JA 39 and JA 42 was also evaluated in chickens of Arbor Akerbreed. These trials were conducted by using basically the same testprotocol as that used for the chickens of Habbared X breed, albeit withthe following modifications:

-   -   i) On day 3 after hatch, the tested groups of chickens received        feed containing 100 ppm of JA 12, JA 39, JA 42 or Coxistac (60        ppm);    -   ii) On day 7 after hatch, the chickens were infected orally by        oocysts containing a mixture of 8 mature sporulated strains,        namely E. mitis, E. hagani, E. praecox, E. acervulina, E.        maxima, E. necatrix, E. tenella and E. brunetti.

For JA 39 and JA 42, the results were essentially the same as thosereported for the trials with the chickens of Habbared X breed (videsupra), whereas the antiparasitic efficacy of JA 12 was very similar tothat of JA 39.

In yet another evaluation of the prophylactic anticoccidial effect ofthe present compounds, additional trials on chickens of Habbared X breedwere performed. The same test protocol as the one previously employedfor this breed of chickens was used, albeit with the following followingmodifications:

-   -   i) On day 8 after hatch, the chickens received feed containing        B700 (100 ppm), JA 3 (200 ppm) or Coxistac (100 ppm);    -   ii) On day 11 after hatch, the chickens were infected orally by        oocysts containing a mixture of 8 mature sporulated strains,        namely E. mitis, E. hagani, E. praecox, E. acervulina, E.        maxima, E. necatrix, E. tenella and E. brunetti.        The results of this evaluation were slightly unexpected.

Both B700 and JA 3 displayed a significant anticoccidial activity,albeit the total number of oocysts during the treatment was higher thanfor the group treated with Coxistac. However, despite the said highernumber of oocysts, the chickens treated with B700 or JA 3 experienced anapproximately 10% increased body weight gain as compared to the Coxistactreated group. Moreover, a similar or even lowered (up to about 10%)feed consumption was observed in the chickens treated with B700 or JA 3.In short, the net effect of the treatment with B700 or JA 3 was clearlybeneficial to the chickens.

Antiparasitic Testing Against Trypanosoma:

The antitrypanosomal activity of the present compounds was evaluated invivo on 40 white albino rats. The rats were divided into 4 groups of 10rats each. The rats were then inoculated intraperitoneally with 10³organisms of T. evansi (isolated from blood of naturally infectedcamels) in accordance with known methodology (see Kolmer, J. A., J.Infect. Dis., 17:78-95 (1915)). The progress of the infection wasmonitored with the aid of standard Giemsa procedure (see Cruickshank,R., Handbook of Bacteriology, E and S Livingstone Ltd., Edinborough andLondon, 1961), whereby peripheral blood samples from the rats wereexamined under microscope. The number of Trypanosoma organisms in everyblood sample was calculated and classified as follows (the numbers beloware given for fields examined on a microscope slide):

-   -   +++=>10 organisms    -   ++=5-10 organisms    -   +=1-4 organisms    -   0=no organisms detected

On day 1 post infection, each group of rats was subcutaneously injectedwith a single dose of tested compound in an amount of 50.0 mg/kg bodyweight. The following drugs were administered:

Group #1: JA 68

Group #2: JA 74

Group #3: JA 110

Group #4: saline solution (control group)

The results of these trials are depicted in Table 9 below:

TABLE 9 Antitrypanosomal effect of JA 68, JA 74 and JA 110 on white ratNumber of T. evansi per examined field at different days post infectionTested animals 1 3 5 7 9 11 13 Group #1 Mouse #1 + 0 0 0 0 0 0 (JA 68)2 + ++ ++ 0 0 0 0 3 + ++ 0 +++ 0 0 0 4 + ++ ++ 0 dead dead dead 5 + ++ 00 0 0 0 6 + ++ 0 0 0 0 0 7 + ++ 0 0 0 0 0 8 + ++ 0 0 0 0 0 9 + ++ 0 0 00 0 10  + ++ 0 0 0 0 0 Group #2 Mouse #1 + ++ +++ dead dead dead dead(JA 74) 2 + ++ 0 0 0 0 0 3 + ++ ++ 0 0 0 0 4 + +++ ++ 0 0 0 0 5 + ++ 0 00 0 0 6 + ++ 0 0 0 0 0 7 + ++ 0 0 0 0 0 8 + ++ 0 0 0 0 0 9 + ++ 0 0 0 00 10  + ++ + 0 0 0 0 Group #3 Mouse #1 + +++ ++ ++ + + 0 (JA 110) 2 + ++++ ++ 0 0 0 3 + ++ ++ ++ 0 0 0 4 + +++ ++ ++ 0 0 0 5 + ++ ++ ++ 0 0 06 + ++ ++ ++ 0 0 0 7 + ++ ++ ++ 0 0 0 8 + ++ ++ ++ 0 0 0 9 + ++ ++ ++ 00 0 10  + ++ ++ ++ 0 0 0 Group #4 Mouse #1 + ++ ++ +++ +++ dead All(control) 2 ++ ++ +++ +++ dead dead animals 3 + +++ +++ +++ +++ +++ dead4 + ++ ++ +++ +++ dead 5 + +++ ++ +++ +++ +++ 6 + ++ ++ +++ +++ +++ 7 +++ ++ +++ +++ +++ 8 + ++ ++ +++ dead dead 9 + ++ ++ +++ +++ +++ 10  + ++++ +++ +++ +++

As supported by the results obtained (vide supra), the tested compoundsare all highly suitable for treatment of Trypanosoma infection as well.

In summary, it should be clear from the present disclosure that thecompounds according to the present invention are versatile new agentsfor antibacterial and/or antiparasitic treatment.

1. A compound having the formula (I):

wherein R₁ is selected from the group consisting of a cyclopropyl groupand an ethyl group; R₂ is selected from the group consisting of H and F;R₃ is selected from the group consisting of a 4-carboxycyclohexyl group,a 4-pyridinylmethyl group, 4-carboxybenzyl group, a 4-carboxyphenylgroup, a [(trifluoromethyl)sulfonyl)]aminopropyl group,2,2-dimethyl-3-[(trifluoromethyl)sulfony]aminopropyl group, a2-[(trifluoromethyl)sulfonyl]aminoethyl group, a 5-bromo-2-pyrldinylgroup, a tetrahydro-2-furanylmethyl group, a 2-(1-pyrrolidinyl)ethylgroup, a 2-naphtylsulfonyl group, a 2-(4-pyridinyl)ethyl group, and a2-(2-pyridinyl)ethyl group; R₄ is selected from the group consisting ofa (tifluoromethyl)sulfonyl group, a 2-thiophenylcarbonyl group, anacetoacetyl group, a 4-fluorophenylsulfonyl group, a 4-nitrophenylgroup, and a tetrahydro-2-furanylmethyl group; or R₃ and R₄, togetherwith the nitrogen to which they are attached, form a piperazinyl groupsubstituted with a methyl group, a (4-nitrophenyl)sulfonyl group, ananilinocarbothioyl group, a 2-naphtylsulfonyl group, a(2,4,6-triisopropyl-phenyl)sulfonyl group, a (4-nitroanilino)carbothioylgroup, a (4-fluoroanilino)carbothioyl group, a(6-chloro-2-pyrazinyl)-4-fluoroanilino carbthioyl group, amesitylsulfonyl group, a benzylsulfonyl group, a(5-chloro-2-thienyl)sulfonyl group, a (4-nitroanilino)carbonyl group, a(2-iodoanilino)carbothioyl group, a (4-cyanoanilino)carbothioyl group, a(4-chlorobenzothioyl) group, a (2,4-dichloroanilino)carbothionyl group,a (2-chloro-4-nitroanilino)carbothioyl group, a 6-chloro-2-pyridinylgroup, a (6-chloro-2-pyridinyl)-4-fluoroanilino)carbothioyl group, a6-chloro-2-pyrazinyl group, and a (trifluoromethyl)sulfonyl group; or R₃and R₄, together with the nitrogen to which they are attached, form apiperidinyl group substituted with a a4-{[anilinocarbothioyl)amino]methyl} group.
 2. A compound according toclaim 1, having the formula (II)

wherein R₃ is selected from the group consisting of a4-carboxycyclohexyl group, a 4-pyridinylmethyl group, a 4-carboxybenzylgroup, a 4-carboxyphenyl group, a[(trifluoromethyl)sulfonyl)]aminopropyl group,2,2-dimethyl-3-[(trifluoromethyl)sulfonyl]aminopropyl group, a2-[(trifluoromethyl)sulfonyl]aminoethyl group, a 5-bromo-2-pyridinylgroup, a tetrahydro-2-furanylmethyl group, a 2-(1-pyrrolidinyl)ethylgroup, a 2-naphtylsulfonyl group, a 2-(4-pyridinyl)ethyl group, a2-(2-pyridinyl)ethyl group; and R₄ is selected from the group consistingof a (trifluoromethyl)sulfonyl group, a 2-thiophenylcarbonyl group, anacetoacetyl group, a 4-fluorophenylsulfonyl group, a 4-nitrophenylgroup, a tetrahydro-2-furanylmethyl group.
 3. A pharmaceuticalcomposition comprising a compound according to claim 1 as activeingredient in association with a pharmaceutically acceptable adjuvant,diluent or carrier.
 4. An animal feed, feed concentrate or drinkingwater comprising a compound according to claim
 1. 5. A method fortreatment of coccidiosis, wherein said method comprises administering toan animal of a therapeutically effective amount of a compound accordingto claim
 1. 6. A pharmaceutical composition comprising a compoundaccording to claim 2 as active ingredient in association with apharmaceutically acceptable adjuvant, diluent or carrier.
 7. An animalfeed, feed concentrate or drinking water comprising a compound accordingto claim
 2. 8. A method for treatment of coccidiosis, wherein saidmethod comprises administering to an animal of a therapeuticallyeffective amount of a compound according to claim
 2. 9. A methodaccording to claim 8, wherein said parasitic disorder is caused byTrypanosoma.